Inhibitors of factor Xa

ABSTRACT

Novel compounds, their salts and compositions related thereto having activity against mammalian factor Xa are disclosed. The compounds are useful in vitro or in vivo for preventing or treating coagulation disorders.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims benefit of priority under 35 U.S.C. § 120to U.S. patent application Ser. No. 09/662,807, which claims benefit ofpriority under 35 U.S.C. § 119(e) to U.S. Provisional Application No.60/154,332 filed on Sep. 17, 1999, which are both herein incorporated intheir entirety by reference.

FIELD OF THE INVENTION

[0002] This invention relates to novel compounds which are potent andhighly selective inhibitors of isolated factor Xa or when assembled inthe prothrombinase complex. These compounds show selectivity for factorXa versus other proteases of the coagulation (e.g. thrombin, fVIIa,fIXa) or the fibrinolytic cascades (e.g. plasminogen activators,plasmin). In another aspect, the present invention relates to novelnon-amidino-containing compounds, their pharmaceutically acceptablesalts, and pharmaceutically acceptable compositions thereof which areuseful as potent and specific inhibitors of blood coagulation inmammals. In yet another aspect, the invention relates to methods forusing these inhibitors as therapeutic agents for disease states inmammals characterized by coagulation disorders.

BACKGROUND OF THE INVENTION

[0003] Hemostasis, the control of bleeding, occurs by surgical means, orby the physiological properties of vasoconstriction and coagulation.This invention is particularly concerned with blood coagulation and waysin which it assists in maintaining the integrity of mammaliancirculation after injury, inflammation, disease, congenital defect,dysfunction or other disruption. Although platelets and bloodcoagulation are both involved in thrombus formation, certain componentsof the coagulation cascade are primarily responsible for theamplification or acceleration of the processes involved in plateletaggregation and fibrin deposition.

[0004] Thrombin is a key enzyme in the coagulation cascade as well as inhemostasis. Thrombin plays a central role in thrombosis through itsability to catalyze the conversion of fibrinogen into fibrin and throughits potent platelet activation activity. Direct or indirect inhibitionof thrombin activity has been the focus of a variety of recentanticoagulant strategies as reviewed by Claeson, G., “Synthetic Peptidesand Peptidomimetics as Substrates and Inhibitors of Thrombin and OtherProteases in the Blood Coagulation System”, Blood Coag. Fibrinol. 5,411-436 (1994). Several classes of anticoagulants currently used in theclinic directly or indirectly affect thrombin (i.e. heparins,low-molecular weight heparins, heparin-like compounds and coumarins).

[0005] A prothrombinase complex, including Factor Xa (a serine protease,the activated form of its Factor X precursor and a member of the calciumion binding, gamma carboxyglutamyl (Gla)-containing, vitamin Kdependent, blood coagulation glycoprotein family), converts the zymogenprothrombin into the active procoagulant thrombin. Unlike thrombin,which acts on a variety of protein substrates as well as at a specificreceptor, factor Xa appears to have a single physiologic substrate,namely prothrombin. Since one molecule of factor Xa may be able togenerate up to 138 molecules of thrombin (Elodi et al., Thromb. Res. 15,617-619 (1979)), direct inhibition of factor Xa as a way of indirectlyinhibiting the formation of thrombin may be an efficient anticoagulantstrategy. Therefore, it has been suggested that compounds whichselectively inhibit factor Xa may be useful as in vitro diagnosticagents, or for therapeutic administration in certain thromboticdisorders, see e.g., WO 94/13693.

[0006] Polypeptides derived from hematophagous organisms have beenreported which are highly potent and specific inhibitors of factor Xa.U.S. Pat. No. 4,588,587 describes anticoagulant activity in the salivaof the Mexican leech, Haementeria officinalis. A principal component ofthis saliva was shown to be the polypeptide factor Xa inhibitor,antistasin (ATS), by Nutt, E. et al., “The Amino Acid Sequence ofAntistasin, a Potent Inhibitor of Factor Xa Reveals a Repeated InternalStructure”, J. Biol. Chem., 263, 10162-10167 (1988). Another potent andhighly specific inhibitor of Factor Xa, called tick anticoagulantpeptide (TAP), has been isolated from the whole body extract of the softtick Ornithidoros moubata, as reported by Waxman, L., et al., “TickAnticoagulant Peptide (TAP) is a Novel Inhibitor of Blood CoagulationFactor Xa” Science, 248, 593-596 (1990).

[0007] Factor Xa inhibitory compounds which are not largepolypeptide-type inhibitors have also been reported including: Tidwell,R. R. et al., “Strategies for Anticoagulation With Synthetic ProteaseInhibitors. Xa Inhibitors Versus Thrombin Inhibitors”, Thromb. Res., 19,339-349 (1980); Turner, A.D. et al., “p-Amidino Esters as IrreversibleInhibitors of Factor IXa and Xa and Thrombin”, Biochemistry, 25,4929-4935 (1986); Hitomi, Y. et al., “Inhibitory Effect of New SyntheticProtease Inhibitor (FUT-175) on the Coagulation System”, Haemostasis,15, 164-168 (1985); Sturzebecher, J. et al., “Synthetic Inhibitors ofBovine Factor Xa and Thrombin. Comparison of Their AnticoagulantEfficiency”, Thromb. Res., 54, 245-252 (1989); Kam, C. M. et al.,“Mechanism Based Isocoumarin Inhibitors for Trypsin and BloodCoagulation Serine Proteases: New Anticoagulants”, Biochemistry, 27,2547-2557 (1988); Hauptmann, J. et al., “Comparison of the Anticoagulantand Antithrombotic Effects of Synthetic Thrombin and Factor XaInhibitors”, Thromb. Haemost., 63, 220-223 (1990); and the like.

[0008] Others have reported Factor Xa inhibitors which are smallmolecule organic compounds, such as nitrogen containing heterocycliccompounds which have amidino substituent groups, wherein two functionalgroups of the compounds can bind to Factor Xa at two of its activesites. For example, WO 98/28269 describes pyrazole compounds having aterminal C(═NH)—NH₂ group; WO 97/21437 describes benzimidazole compoundssubstituted by a basic radical which are connected to a naphthyl groupvia a straight or branched chain alkylene, —C(═O) or —S(═O)₂ bridginggroup; WO 99/10316 describes compounds having a4-phenyl-N-alkylamidino-piperidine and4-phenoxy-N-alkylamidino-piperidine group connected to a 3-amidinophenylgroup via a carboxamidealkyleneamino bridge; and EP 798295 describescompounds having a 4-phenoxy-N-alkylamidino-piperidine group connectedto an amidinonaphthyl group via a substituted or unsubstitutedsulfonamide or carboxamide bridging group.

[0009] There exists a need for effective therapeutic agents for theregulation of hemostasis, and for the prevention and treatment ofthrombus formation and other pathological processes in the vasculatureinduced by thrombin such as restenosis and inflammation. In particular,there continues to be a need for compounds which selectively inhibitfactor Xa or its precursors. Compounds are needed which selectively orpreferentially bind to Factor Xa. Compounds with a higher affinity forbinding to Factor Xa than to thrombin are desired, especially thosecompounds having good bioavailability or other pharmacologicallydesirable properties.

SUMMARY OF THE INVENTION

[0010] The present invention relates to novel compounds which inhibitfactor Xa, their pharmaceutically acceptable isomers, salts, hydrates,solvates and prodrug derivatives, and pharmaceutically acceptablecompositions thereof which have particular biological properties and areuseful as potent and specific inhibitors of blood coagulation inmammals. In another aspect, the invention relates to methods of usingthese inhibitors as diagnostic reagents or as therapeutic agents fordisease states in mammals which have coagulation disorders, such as inthe treatment or prevention of any thrombotically mediated acutecoronary or cerebrovascular syndrome, any thrombotic syndrome occurringin the venous system, any coagulopathy, and any thrombotic complicationsassociated with extracorporeal circulation or instrumentation, and forthe inhibition of coagulation in biological samples.

[0011] In certain embodiments, this invention relates to novel compoundswhich are potent and highly selective inhibitors of isolated factor Xawhen assembled in the prothrombinase complex. These compounds showselectivity for factor Xa versus other proteases of the coagulationcascade (e.g. thrombin, etc.) or the fibrinolytic cascade, and areuseful as diagnostic reagents as well as antithrombotic agents.

[0012] In one embodiment, the present invention provides compoundscomprising a five-membered heterocyclic ring structure having from 1-4hetero atoms selected from the group consisting of N, O and S or abicyclic ring system comprising the 5-membered heterocyclic ringstructure wherein the bicyclic ring structure may have 1-5 hetero atomsselected from the group consisting of N, O and S, and wherein theoverall compound has an essentially neutral pH. The compounds accordingto the invention are potent and selective inhibitors of factor Xa versusother proteases of the coagulation cascade (e.g. thrombin, etc.) or thefibrinolytic cascade, and are useful as diagnostic reagents as well asantithrombotic agents. Particular embodiments of the compounds of thepresent invention are set forth below as preferred embodiments andinclude all pharmaceutically acceptable isomers, salts, hydrates,solvates and prodrug derivatives thereof.

[0013] In certain aspects of this invention, compounds are providedwhich are useful as diagnostic reagents. In another aspect, the presentinvention includes pharmaceutical compositions comprising apharmaceutically effective amount of the compounds of this invention anda pharmaceutically acceptable carrier. In yet another aspect, thepresent invention includes methods comprising using the above compoundsand pharmaceutical compositions for preventing or treating diseasestates characterized by disorders of the blood coagulation process inmammals, or for preventing coagulation in stored blood products andsamples. Optionally, the methods of this invention compriseadministering the pharmaceutical composition in combination with anadditional therapeutic agent such as an antithrombotic and/or athrombolytic agent and/or an anticoagulant.

[0014] The preferred compounds also include their pharmaceuticallyacceptable isomers, hydrates, solvates, salts and prodrug derivatives.

DETAILED DESCRIPTION OF THE INVENTION

[0015] Definitions

[0016] In accordance with the present invention and as used herein, thefollowing terms are defined with the following meanings, unlessexplicitly stated otherwise.

[0017] The term “alkenyl” refers to a trivalent straight chain orbranched chain unsaturated aliphatic radical. The term “alkinyl” (or“alkynyl”) refers to a straight or branched chain aliphatic radical thatincludes at least two carbons joined by a triple bond. If no number ofcarbons is specified alkenyl and alkinyl each refer to radicals havingfrom 2-12 carbon atoms.

[0018] The term “alkyl” refers to saturated aliphatic groups includingstraight-chain, branched-chain and cyclic groups having the number ofcarbon atoms specified, or if no number is specified, having up to 12carbon atoms. The term “cycloalkyl” as used herein refers to a mono-,bi-, or tricyclic aliphatic ring having 3 to 14 carbon atoms andpreferably 3 to 7 carbon atoms.

[0019] As used herein, the terms “carbocyclic ring structure” and “C₃₋₁₆carbocyclic mono, bicyclic or tricyclic ring structure” or the like areeach intended to mean stable ring structures having only carbon atoms asring atoms wherein the ring structure is a substituted or unsubstitutedmember selected from the group consisting of: a stable monocyclic ringwhich is aromatic ring (“aryl”) having six ring atoms; a stablemonocyclic non-aromatic ring having from 3 to 7 ring atoms in the ring;a stable bicyclic ring structure having a total of from 7 to 12 ringatoms in the two rings wherein the bicyclic ring structure is selectedfrom the group consisting of ring structures in which both of the ringsare aromatic, ring structures in which one of the rings is aromatic andring structures in which both of the rings are non-aromatic; and astable tricyclic ring structure having a total of from 10 to 16 atoms inthe three rings wherein the tricyclic ring structure is selected fromthe group consisting of: ring structures in which three of the rings arearomatic, ring structures in which two of the rings are aromatic andring structures in which three of the rings are non-aromatic. In eachcase, the non-aromatic rings when present in the monocyclic, bicyclic ortricyclic ring structure may independently be saturated, partiallysaturated or fully saturated. Examples of such carbocyclic ringstructures include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, adamantyl, cyclooctyl, [3.3.0 ]bicyclooctane,[4.3.0 ]bicyclononane, [4.4.0]bicyclodecane (decalin),[2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl,or tetrahydronaphthyl (tetralin). Moreover, the ring structuresdescribed herein may be attached to one or more indicated pendant groupsvia any carbon atom which results in a stable structure. The term“substituted” as used in conjunction with carbocyclic ring structuresmeans that hydrogen atoms attached to the ring carbon atoms of ringstructures described herein may be substituted by one or more of thesubstituents indicated for that structure if such substitution(s) wouldresult in a stable compound.

[0020] The term “aryl” which is included with the term “carbocyclic ringstructure” refers to an unsubstituted or substituted aromatic ring,substituted with one, two or three substituents selected fromloweralkoxy, loweralkyl, loweralkylamino, hydroxy, aminoloweralkyl,hydroxyloweralkyl, halogen, cyano, hydroxyl, mercapto, nitro,thioalkoxy, carboxaldehyde, carboxyl, carboalkoxy and carboxamide,including but not limited to carbocyclic aryl, heterocyclic aryl, andbiaryl groups and the like, all of which may be optionally substituted.Preferred aryl groups include phenyl, halophenyl, loweralkylphenyl,napthyl, biphenyl, phenanthrenyl and naphthacenyl.

[0021] The term “arylalkyl” which is included with the term “carbocyclicaryl” refers to one, two, or three aryl groups having the number ofcarbon atoms designated, appended to an alkyl group having the number ofcarbon atoms designated. Suitable arylalkyl groups include, but are notlimited to, benzyl, picolyl, naphthylmethyl, phenethyl, benzyhydryl,trityl, and the like, all of which may be optionally substituted.

[0022] As used herein, the term “heterocyclic ring” or “heterocyclicring system” is intended to mean a substituted or unsubstituted memberselected from the group consisting of stable monocyclic ring having from5-7 members in the ring itself and having from 1 to 4 hetero ring atomsselected from the group consisting of N, O and S; a stable bicyclic ringstructure having a total of from 7 to 12 atoms in the two rings whereinat least one of the two rings has from 1 to 4 hetero atoms selected fromN, O and S, including bicyclic ring structures wherein any of thedescribed stable monocyclic heterocyclic rings is fused to a hexane orbenzene ring; and a stable tricyclic heterocyclic ring structure havinga total of from 10 to 16 atoms in the three rings wherein at least oneof the three rings has from 1 to 4 hetero atoms selected from the groupconsisting of N, O and S. Any nitrogen and sulfur atoms present in aheterocyclic ring of such a heterocyclic ring structure may be oxidized.Unless indicated otherwise the terms “heterocyclic ring” or“heterocyclic ring system” include aromatic rings, as well asnon-aromatic rings which can be saturated, partially saturated or fullysaturated non-aromatic rings. Also, unless indicated otherwise the term“heterocyclic ring system” includes ring structures wherein all of therings contain at least one hetero atom as well as structures having lessthan all of the rings in the ring structure containing at least onehetero atom, for example bicyclic ring structures wherein one ring is abenzene ring and one of the rings has one or more hetero atoms areincluded within the term “heterocyclic ring systems” as well as bicyclicring structures wherein each of the two rings has at least one heteroatom. Moreover, the ring structures described herein may be attached toone or more indicated pendant groups via any hetero atom or carbon atomwhich results in a stable structure. Further, the term “substituted”means that one or more of the hydrogen atoms on the ring carbon atom(s)or nitrogen atom(s) of the each of the rings in the ring structuresdescribed herein may be replaced by one or more of the indicatedsubstituents if such replacement(s) would result in a stable compound.Nitrogen atoms in a ring structure may be quaternized, but suchcompounds are specifically indicated or are included within the term “apharmaceutically acceptable salt” for a particular compound. When thetotal number of O and S atoms in a single heterocyclic ring is greaterthan 1, it is preferred that such atoms not be adjacent to one another.Preferably, there are no more that 1 O or S ring atoms in the same ringof a given heterocyclic ring structure.

[0023] Examples of monocylic and bicyclic heterocylic ring systems, inalphabetical order, are acridinyl, azocinyl, benzimidazolyl,benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl,benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl,benzisothiazolyl, benzimidazalinyl, carbazolyl, 4aH-carbazolyl,carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl,2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl,furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, lH-indazolyl,indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuiranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl(benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl,pyroazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pryidooxazole,pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl,pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl,quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,1,3,4-triazolyl and xanthenyl. Preferred heterocyclic ring structuresinclude, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl,pyrazolyl, pyrrolidinyl, imidazolyl, indolyl, benzimidazolyl,lH-indazolyl, oxazolinyl, or isatinoyl. Also included are fused ring andspiro compounds containing, for example, the above heterocylic ringstructures.

[0024] As used herein the term “aromatic heterocyclic ring system” hasessentially the same definition as for the monocyclic and bicyclic ringsystems except that at least one ring of the ring system is an aromaticheterocyclic ring or the bicyclic ring has an aromatic or non-aromaticheterocyclic ring fused to an aromatic carbocyclic ring structure.

[0025] The terms “halo” or “halogen” as used herein refer to Cl, Br, For I substituents. The term “haloalkyl”, and the like, refer to analiphatic carbon radicals having at least one hydrogen atom replaced bya Cl, Br, F or I atom, including mixtures of different halo atoms.Trihaloalkyl includes trifluoromethyl and the like as preferredradicals, for example.

[0026] The term “methylene” refers to —CH₂—.

[0027] The term “pharmaceutically acceptable salts” includes salts ofcompounds derived from the combination of a compound and an organic orinorganic acid. These compounds are useful in both free base and saltform. In practice, the use of the salt form amounts to use of the baseform; both acid and base addition salts are within the scope of thepresent invention.

[0028] “Pharmaceutically acceptable acid addition salt” refers to saltsretaining the biological effectiveness and properties of the free basesand which are not biologically or otherwise undesirable, formed withinorganic acids such as hydrochloric acid, hydrobromic acid, sulfuricacid, nitric acid, phosphoric acid and the like, and organic acids suchas acetic acid, trifluoroacetic acid, propionic acid, glycolic acid,pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid,fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid,mandelic acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicyclic acid and the like.

[0029] “Pharmaceutically acceptable base addition salts” include thosederived from inorganic bases such as sodium, potassium, lithium,ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminumsalts and the like. Particularly preferred are the ammonium, potassium,sodium, calcium and magnesium salts. Salts derived from pharmaceuticallyacceptable organic nontoxic bases include salts of primary, secondary,and tertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines and basic ion exchange resins, such asisopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine,dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,hydrabamine, choline, betaine, ethylenediamine, glucosamine,methylglucamine, theobromine, purines, piperizine, piperidine,N-ethylpiperidine, polyamine resins and the like. Particularly preferredorganic nontoxic bases are isopropylamine, diethylamine, ethanolamine,trimethamine, dicyclohexylamine, choline, and caffeine.

[0030] “Biological property” for the purposes herein means an in vivoeffector or antigenic function or activity that is directly orindirectly performed by a compound of this invention that are oftenshown by in vitro assays. Effector fuinctions include receptor or ligandbinding, any enzyme activity or enzyme modulatory activity, any carrierbinding activity, any hormonal activity, any activity in promoting orinhibiting adhesion of cells to an extracellular matrix or cell surfacemolecules, or any structural role. Antigenic functions includepossession of an epitope or antigenic site that is capable of reactingwith antibodies raised against it.

[0031] In the compounds of this invention, carbon atoms bonded to fournon-identical substituents are asymmetric. Accordingly, the compoundsmay exist as diastereoisomers, enantiomers or mixtures thereof. Thesyntheses described herein may employ racemates, enantiomers ordiastereomers as starting materials or intermediates. Diastereomericproducts resulting from such syntheses may be separated bychromatographic or crystallization methods, or by other methods known inthe art. Likewise, enantiomeric product mixtures may be separated usingthe same techniques or by other methods known in the art. Each of theasymmetric carbon atoms, when present in the compounds of thisinvention, may be in one of two configurations (R or S) and both arewithin the scope of the present invention.

[0032] Preferred Embodiments

[0033] The invention provides a compound of the formula (I):

A-Q-D-E-G-J-X

[0034] wherein:

[0035] A is selected from:

[0036] —C₁₋₆alkyl;

[0037] —C₃₋₈cycloalkyl;

[0038] phenyl, which is substituted with 0-2 R¹ groups;

[0039] naphthyl, which is substituted with 0-2 R¹ groups; and

[0040] a 3-10 membered aromatic or non-aromatic heterocyclic ring systemwhich may be a monocyclic ring system or a fuised bicyclic ring system,wherein the heterocyclic ring system contains 1-4 heteroatoms selectedfrom N, O and S and is substituted with 0-2 R¹ groups;

[0041] R¹ is selected from:

[0042] Halo, —CN, —C(═O)—N(R², R³), —NO₂, —SO₂N(R², R³), —SO₂R²,—(CH₂)_(m)NR²R , —(CH₂)_(m)—C(═NR³)—R², (CH₂)_(m)—C(═NR²)N(R²,R³),—(CH₂)_(m)—N(R²)—C(═NR²)—N(R²,R³), —(CH₂)_(m)NR²—C₃₋₆heterocyclics,C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloalkyl,C₀₋₄alkylC₃₋₈cycloalkyl, —CF₃, —OR², and a 5-6 membered heterocyclicsystem containing from 1-4 heteroatoms selected from N, O and S, whereinfrom 1-4 hydrogen atoms on the heterocyclic system may be independentlyreplaced with a member selected from the group consisting of halo,C₁-C₄-alkyl, —CN C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloalkyl,C₀₋₄alkylC₃₋₈cycloalkyl and —NO₂;

[0043] R² and R³ are independently selected from the group consistingof:

[0044] —H, —C₁₋₆alkyl, —C₁₋₆alkyloxy, —C₂₋₆alkenyl, —C₂₋₆alkynyl,—C₃₋₈cycloalkyl, —C₀₋₆alkylC₃₋₈cycloalkyl and —C₀₋₆alkyl-(carbocyclicaryl), wherein from 0-4 hydrogen atoms on the ring atoms of thecarbocyclic aryl moiety may be independently replaced with a memberselected from the group consisting of halo, —C₁₋₄alkyl, —C₂₋₆alkenyl,—C₂₋₆alkynyl, —C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl, —S(═O)₂—OH,—CN, —CF₃ and —NO₂;

[0045] or R² and R³ taken together can form a 3-8 membered cycloalkyl ora heterocyclic ring system, wherein the heterocyclic ring system mayhave from 3 to 10 ring atoms, with 1 to 2 rings being in the ring systemand contain from 1-4 heteroatoms selected from N, O and S, wherein from1-4 hydrogen atoms on the heterocyclic ring system may be independentlyreplaced with a member selected from the group consisting of halo,C₁-C₄-alkyl, —CN —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,—C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl and —NO₂;

[0046] m is an integer of 0-2;

[0047] Q is selected from the group consisting of:

[0048] a direct link, divalent —C₁₋₄alkyl, divalent —C₂₋₄alkenyl,divalent —C₂₋₄alkynyl, —C(═O)—, —C(═NH)—, —C(═NMe)—, —N(—R⁴)—,—N(—R⁴)—CH₂—, —C(═O)—N(—R⁴)—, —N(—R⁴)—C(═O)—, —S(═O)₂—, —O—,—S(═O)₂—N(—R⁴)— and —N(—R⁴)—S(═O)₂—, wherein one or more hydrogens oneach of the divalent C₁₋₄alkyl, divalent C₂₋₄alkenyl and divalentC₂₋₄alkynyl moieties can be replaced with a —R⁴ group;

[0049] R⁴ is selected from the group consisting of:

[0050] —H, —C₁₋₆alkyl, —C₁₋₆alkyloxy, —C₂₋₆alkenyl, —C₂₋₆alkynyl,—C₃₋₈cycloalkyl, —C₀₋₆alkyIC₃₋₈cycloalkyl and —C₀₋₆alkyl-(carbocyclicaryl), wherein from 0-4 hydrogen atoms on the ring atoms of thecarbocyclic aryl moiety may be independently replaced with a memberselected from the group consisting of halo, —C₁₋₄alkyl, —C₂₋₆alkenyl,—C₂₋₆alkynyl, —C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl, —S(═O)₂—OH,—CN, —CF₃ and —NO₂;

[0051] D is selected from the group consisting of:

[0052] a direct link;

[0053] phenyl, which is substituted with 0-2 R^(1a) groups; and

[0054] a 5-10 membered aromatic or non-aromatic heterocyclic ring systemwhich may be a monocyclic ring system or a fused bicyclic ring system,wherein the heterocyclic ring system contains 1-4 heteroatoms selectedfrom N, O and S and the ring system is substituted with 0-2 R^(1a)groups;

[0055] R^(1a) is selected from the group consisting of:

[0056] halo, —C₁₋₆alkyl, —C₁₋₆alkyloxy, —C₂₋₆alkenyl, —C₂₋₆alkynyl,—C₃₋₈cycloalkyl, —C₀₋₆alkylC₃₋₈cycloalkyl, —S(═O)₂—OH, —CN, —NO₂,—(CH₂)_(n)—N(R^(2a), —R^(3a)), —S(═O)₂—N(—R^(2a), —R^(3a)),S(═O)₂—R^(2a), —CF₃, (CH₂)_(n)OR^(2a), —C(═O)—O—R^(2a),—C(═O)—N(—R^(2a)—R^(3a)), —C(═NH)—N(—R^(2a), —R^(3a)),—C(═NMe)—N(—R^(2a)R^(3a)), 2-imidazolin-2-yl, 1-methyl-2-imidazolin-2-yland a 5-6 membered aromatic heterocyclic ring containing 1-4 heteroatomsselected from N, O and S and —C₀₋₆alkyl-(carbocyclic aryl), wherein from0-4 hydrogen atoms on the ring atoms of the aromatic heterocyclic ringand the carbocyclic aryl moiety may be independently replaced with amember selected from the group consisting of halo, —C₁₋₄alkyl,—C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl,—CN, —CF₃ and —NO₂;

[0057] R^(2a) and R^(3a) are independently selected from the groupconsisting of:

[0058] —H, —C₁₋₆alkyl, —C₁₋₆alkyloxy, —C₂₋₆alkenyl, —C₂₋₆alkynyl,—C₃₋₈cycloalkyl, —C₀₋₆alkylC₃₋₈cycloalkyl and —C₀₋₆alkyl-(carbocyclicaryl), wherein from 0-4 hydrogen atoms on the ring atoms of thecarbocyclic aryl moiety may be independently replaced with a memberselected from the group consisting of halo, —C₁₋₄alkyl, —C₂₋₆alkenyl,—C₂₋₆alkynyl, —C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl, —S(═O)₂—OH,—CN, —CF₃ and —NO₂;

[0059] n is an integer of 0-2;

[0060] E is selected from the group consisting of:

[0061] a direct link, (CH₂)_(q)—C(═O),—(CH₂)_(q)—N(—R⁵)—C(═O)—(CH₂)_(x)—, —(CH₂)_(q)—C(═O)—N(—R⁵)—(CH₂)_(q)—,—(CH₂)_(q)—N(—R⁵)—(CH₂)_(x)—, —(CH₂)_(q)—N(R⁵)CO—NR⁶(CH₂), and —SO₂—;

[0062] q and x are independently an integer of 0-2;

[0063] R⁵ and R⁶ are independently selected from the group consistingof:

[0064] —H, —C₁₋₆alkyl, —C₁₋₆alkyloxy, —C₂₋₆alkenyl, —C₂₋₆alkynyl,—C₃₋₈cycloalkyl, —C₀₋₆alkylC₃₋₈cycloalkyl, —C₁₋₄alkyl—C(═O)—OH,—C₀₋₆alkyl-(carbocyclic aryl), —C₀₋₄alkyl-(monocyclic heteroaryl) and—C₀₋₄alkyl—C(═O)—O—C₁₋₄alkyl, wherein from 0-4 hydrogen atoms on thering atoms of the carbocyclic aryl moiety and the monocyclic heteroarylmoieties may be independently replaced with a member selected from thegroup consisting of halo, —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,—C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl, —S(═O)₂—OH, —CN, —CF₃ and—NO₂;

[0065] G is selected from the group consisting of:

[0066] phenyl, which is substituted with 0-2 R^(1b) groups; and

[0067] a 5-6 membered aromatic heterocyclic ring containing 1-4 heteroatoms selected from N, O and S wherein the heterocyclic ring issubstituted with 0-2 R^(1b) groups;

[0068] R^(1b) is independently selected from the group consisting of:

[0069] halo, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,—C₀₋₆alkylC₃₋₈cycloalkyl, —C₁₋₄alkyl—C(═O)—OH, —CN, —NO₂, —S(═O)₂—OH,—N(—R^(2b), —R^(3b)), —C(═O)—N(—R^(2b), —R^(3b)), —S(═O)₂—N(—R^(2b),—R^(3b)), —S(═O)₂—R^(2b), —CF₃, —O—R^(2b), —O—CH₂CH₂—O—R^(2b),—O—CH₂—C(═O)—O—R^(2b), —N(—R^(2b))—CH₂—CH₂—O—R^(2b),—N(—CH₂—CH₂—O—R^(2b))₂, —N(R^(2b))—C(═O)—R^(3b),—N(—R^(2b))—S(═O)₂—R^(3b), and a 5-6 membered heterocyclic ringcontaining 1-4 heteroatoms selected from N, O and S substituted with 0-4R^(1b′) groups;

[0070] alternatively, when two R^(1b) may be present on adjacent ringatoms of G and combine to form a benzene ring substituted with 0-4R^(1b′) groups or a 5-6 membered aromatic or non-aromatic heterocyclicring having 1-3 heteroatoms selected from N, O and S substituted with0-4 R^(1b′) groups;

[0071] in a second alternative, one of the R^(1b) groups of G can cylizewith the —N-R⁵ group of E to form a 5-7 membered heterocyclic ringcontaining 1-4 heteroatoms selected from N, O and S, which is subtitutedwith 0-4 R^(1b′) groups, wherein two of the R groups attached to thesame ring carbon may form a (═O) group;

[0072] R^(2b) and R^(3b) are independently selected from the groupconsisting of:

[0073] —H, —C₁₋₆alkyl, —C₁₋₆alkyloxy, —C₂₋₆alkenyl, —C₂₋₆alkynyl,—C₃₋₈cycloalkyl, —C₀₋₆alkylC₃₋₈cycloalkyl and —C₀₋₆alkyl-(carbocyclicaryl), wherein from 0-4 hydrogen atoms on the ring atoms of thecarbocyclic aryl moiety may be independently replaced with a memberselected from the group consisting of halo, —C₁₋₄alkyl, —C₂₋₆alkenyl,—C₂₋₆alkynyl, —C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl, —S(═O)₂—O, —CN,—CF₃ and —NO₂;

[0074] R^(1b′) is independently selected from the group consisting of:

[0075] halo, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,—C₀₋₆alkylC₃₋₈cycloalkyl, —C₁₋₄alkyl—C(═O)—OH, —CN, —NO₂, —S(═O)₂—OH,N(—R^(2b′), —R^(3b′)), —C(═O)—N(—R^(2b′), —R^(3b′)), —S(═O)₂—N(—R^(2b′),—R^(3b′)), —S(═O)₂—R^(2b′), —CF₃, —O—R^(2b′), —O—CH₂—CH₂—O—R^(2b′),—O—CH₂—C(═O)—O—R^(2b′), —N(—R^(2b′))—CH₂—CH₂—O—R^(2b′),—N(—CH₂—CH₂—O—R^(2b′))₂, —N(—R^(2b′))—C(═O)—R^(3b′) and—N(—R^(2b′))—S(═O)₂—R^(3b′);

[0076] R^(2b′) and R^(3b′) are independently selected from the groupconsisting of: —H, —C₁₋₆alkyl, —C₁₋₆alkoxy, —C₂₋₆alkenyl, —C₂₋₆alkynyl,—C₃₋₈cycloalkyl, —C₀₋₆alkylC₃₋₈cycloalkyl and —C₀₋₆alkyl-(carbocyclicaryl), wherein from 0-4 hydrogen atoms on the ring atoms of thecarbocyclic aryl moiety may be independently replaced with a memberselected from the group consisting of halo, —C₁₋₄alkyl, —C₂₋₆alkenyl,—C₂₋₆alkynyl, —C₃₋₈cycloakyl, —C₀₋₄alkylC₃₋₈cycloalkyl, —S(═O)₂—OH, —CN,—CF₃ and —NO₂;

[0077] J is selected from the group consisting of:

[0078] a direct link, —S(═O)₂—, —C(═O)—, —N(—R⁷)—S(═O)₂—,—C(═O)—N(—R⁷)—S(═O)₂—, —C(═O)—N(—R⁷)—(CH₂)_(y), —S(═O)₂—N(—R⁷)—(CH₂)_(y)—, and —N(—R⁷)—C(═O)—(CH₂)_(y)—;

[0079] y is an integer of 0-2;

[0080] R⁷ is selected from the group consisting of:

[0081] —H, —C₂₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,—C₀₋₆alkylC₃₋₈cycloalkyl, —C₁₋₆alkyl—C(═O)—OH, —C₁₋₆alkyl-OH,—C₁₋₆alkyl-O—C₁₋₄alkyl, —C₀₋₄alkyl-(carbocyclic aryl),—C₀₋₄alkyl-(monocyclic or bicyclic heterocyclic ring system having from0-4 heteroatoms selected from the group consisting of N, O and S),—CH₂—C(═O)—O—C₁₋₄alkyl and —CH₂—C(═O)—O—C₁₋₄alkyl-(carbocyclic aryl),wherein from 0-4 hydrogen atoms on the ring atoms of the carbocyclicaryl moiety or the heterocyclic ring system may be independentlyreplaced with a member selected from the group consisting of halo,—C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,—C₀₋₄alkylC₃₋₈cycloalkyl, —S(═O)₂—OH, —CN, —CF₃ and —NO₂;

[0082] X is selected from the group consisting of:

[0083] phenyl, which is substituted with 0-3 R^(1c) groups;

[0084] naphthyl, which is substituted with 0-3 R^(1c) groups;

[0085] a 6-membered heteroaromatic ring containing from 1-2 nitrogenatoms, wherein the ring is substituted with 0-3 R^(1c) groups; and

[0086] a fused heterobicyclic ring system, wherein the ring systemcontains 1-3 heteroatoms selected from N, O and S and is substitutedwith 0-3 R^(1c) groups;phenyl, which is substituted with 0-3 R^(1c)groups;

[0087] R^(1c) is independently selected from the group consisting of:

[0088] halo, —CF₃, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,—C₃₋₈cycloalkyl, —C₀₋₆alkylC₃₋₈cycloalkyl, —C₁₋₄alkyl—C(═O)—OH, —CF₃,—CN, —NO₂, —(CH₂)_(z)—N(—R^(2c), —R^(3c)), —C(═O)—N(—R^(2c), —R^(3c)),—C(═NH)—N(—R^(2c), —R^(3c)), —C(═NMe)—N(—R^(2c), —R^(3c)),—S(═O)₂—N(—R^(2c), —R^(3c)), —S(═O)₂—R^(2c)—S(═O)₂—OH, —CF₃, —O—R^(2c),—O(—CH₂)_(z)—O—R^(2c), —O(—CH₂)_(z)—C(═O)—O—R^(2c), —N(—R^(2c)),—O(—CH₂)_(z)—O—R^(2c), —N[(—CH₂)_(z)—O—R^(2c)]₂,—(CH₂)_(z)—N(—R^(2c))—C(═O)R^(3c), —(CH₂)_(z)—N(—R^(2c))—S(═O)₂—R^(2c),and a 5-6 membered heterocyclic ring containing 1-4 heteroatoms selectedfrom N, O and S;

[0089] z is an integer of 0-4;

[0090] R^(2c) and R^(3c) are independently selected from the groupconsisting of:

[0091] —H, —C₁₋₆alkyl, —C₁₋₆alkyloxy, —C₂₋₆alkenyl, —C₂₋₆alkynyl,—C₃₋₈cycloalkyl, —C₀₋₆alkylC₃₋₈cycloalkyl and —C₀₋₆alkyl-(carbocyclicaryl), wherein from 0-4 hydrogen atoms on the ring atoms of thecarbocyclic aryl moiety may be independently replaced with a memberselected from the group consisting of halo, —C₁₋₄alkyl, —C₂₋₆alkenyl,—C₂₋₆alkynyl, —C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl, —S(═O)₂—OH,—CN, —CF₃ and —NO₂;

[0092] and all pharmaceutically acceptable isomers, salts, hydrates,solvates and prodrug derivatives thereof.

[0093] The invention also provides a compound of the formula (I):

A-Q-D-E-G-J-X

[0094] wherein:

[0095] A is selected from the group consisting of:

[0096] —C₁₋₆alkyl and —C₃₋₈cycloalkyl;

[0097] phenyl, which is substituted with 0-2 R¹ groups;

[0098] naphthyl, which is substituted with 0-2 R¹ groups; and

[0099] a 3-10 membered aromatic or non-aromatic heterocyclic ring systemwhich may be a monocyclic ring system or a fused bicyclic ring system,wherein the heterocyclic ring system contains 1-4 heteroatoms selectedfrom N, O and S and is substituted with 0-2 R¹ groups;

[0100] R¹ is independently selected from the group consisting of:

[0101] halo, —C₁₋₄alkyl, —CN, —NO₂, —(CH₂)_(m)—N(—R², —R³),—C(═O)—N(—R²,—R³), —S(═O)₂—N(—R²,—R³), —S(═O)₂—R², (CH₂)_(m)C(═NR³)—R²,—(CH₂)_(m)—C(═NR²)—N(R²,R³), —(CH₂)_(m)—N(R²)—C(NR²)—N(R²,R³), —CF₃,—(CH₂)_(m)—O—R² and a 5-6 membered aromatic heterocyclic ring containing1-4 heteroatoms selected from N, O and S;

[0102] R² and R³ are independently selected from the group consistingof:

[0103] —H, —C₁₋₄alkyl and —C₀₋₄alkyl-(carbocyclic aryl);

[0104] m is an integer of 0-2;

[0105] Q is selected from the group consisting of:

[0106] a direct link, —C₁₋₄alkyl, —C₂₋₄alkenyl, —C₂₋₄alkynyl, —C(═O)—,—C(═NH)—, —C(═NMe)—, —N(—R⁴)—, —N(—R⁴)—CH₂—, —NH—C(═NH)—, —NH—C(═NMe)—,—C(═O)—N(—R⁴)—, —N(—R⁴)—C(═O)—, —S(═O)₂—, —O—, —S(═O)₂—N(—R⁴)— and—N(—R⁴)—S(═O)₂;

[0107] R⁴ is selected from the group consisting of:

[0108] —H, —C₁₋₄alkyl and —C₀₋₄alkyl-(carbocyclic aryl);

[0109] D is selected from the group consisting of:

[0110] a direct link;

[0111] phenyl, which is substituted with 0-2 R^(1a) groups; and

[0112] a 5-10 membered aromatic or non-aromatic heterocyclic ring systemwhich may be a monocyclic ring system or a fused bicyclic ring system,wherein the heterocyclic ring system contains 1-4 heteroatoms selectedfrom N, O and S and the ring system is substituted with 0-2 R^(1a)groups;

[0113] R^(1a) is independently selected from the group consisting of:

[0114] halo, —C₁₋₄alkyl, —CN, —NO₂, —(CH₂),—N(—R^(2a), —R^(3a)),—S(═O)₂—N(—R^(2a), —R^(3a)), —S(═O)₂—R^(2a), —CF₃, —(CH₂)_(n)—OR^(2a),—C(═O)—O—R^(2a), —C(═O)—N(—R^(2a), —R^(3a)) and a 5-6 membered aromaticheterocyclic ring containing 1-4 heteroatoms selected from N, O and S;

[0115] n is an integer of 0-2;

[0116] R^(2a) and R^(3a) are independently selected from the groupconsisting of:

[0117] —H, —C₁₋₄alkyl, and —C₁₋₄alkyl-(carbocyclic aryl);

[0118] E is selected from the group consisting of:

[0119] a direct link, —(CH₂)_(q)—C(═O)—,—(CH₂)_(q)—N(—R⁵)—C(═O)—(CH₂)_(x)—, —(CH₂)_(q)—C(═O)—N(—R⁵)—(CH₂)_(x)—,—(CH₂)_(q)—N(—R⁵)—(CH₂)_(x)—, —(CH₂)_(q)—N(R⁵)CO—NR⁶(CH₂)_(x)— and—SO₂—;

[0120] q and x are independently an integer of 0-2;

[0121] R⁵ and R⁶ are independently selected from the group consistingof:

[0122] —H, —C₁₋₄alkyl, —C₀₋₄alkyl-(carbocyclic aryl),

[0123] —C₀₋₄alkyl-(monocyclic heteroaryl), —C₁₋₄alkyl—C(═O)—OH and

[0124] —C₁₋₄alkyl—C(═O)—O—C₁₋₄alkyl;

[0125] G is selected from the group consisting of:

[0126] phenyl, which is substituted with 0-2 R^(1b) groups; and

[0127] a 5-6 membered aromatic heterocyclic ring containing 1-4 heteroatoms selected from O, S and N, wherein the heterocyclic ring issubstituted with 0-2 R^(1b) groups;

[0128] R^(1b) is independently selected from the group consisting of:

[0129] halo, —C₁₋₄alkyl, —CN, —NO₂, —N(R^(2b), —R^(3b)),—C(═O)—N(—R^(2b), —R^(3b)), —S(═O)₂—N(—R^(2b), —R^(3b)), —S(═O)₂—R^(2b),—CF₃, —O—R^(2b), —O—CH₂—CH₂—O—R^(2b), —O—CH₂—C(═O)—O—R^(2b), CH₂—CH₂—N(—CH₂—CH₂R^(2b))₂, —N(—R^(2b))—C(═O)—R^(3b), —N(—R^(2b))—S(═O)₂—R^(2b)and a 5-6 membered heterocyclic ring containing 1-4 heteroatoms selectedfrom N, O and S;

[0130] alternatively, when two R may be present on adjacent ring atomsof G and combine to form a benzene ring substituted with 0-4 R^(1b′)groups or a 5-6 membered aromatic or non-aromatic heterocyclic ringhaving 1-3 heteroatoms selected from N, O and S substituted with 0-4R^(1b′) groups;

[0131] in a second alternative, one of the R^(1b) groups of G can cylizewith the —N—R⁵ group of E to form a 5-7 membered saturated, unsaturatedor partially unsaturated heterocyclic ring containing 1-4 heteroatomsselected from N, O and S, which is substituted with 0-4 R^(1b′) groups,wherein two of the R^(1b′) groups attached to the same ring carbon mayform a (═O) group;

[0132] R^(2b) and R^(3b) are independently selected from the groupconsisting of:

[0133] —H, —C₁₋₄alkyl and —C₁₋₄alkyl-(carbocyclic aryl);

[0134] R^(1b′) is independently selected from the group consisting of:

[0135] halo, —C₁₋₄alkyl, —CN, —NO₂, —N(—R^(2b), —R^(3b)),—C(═O)—N(—R^(2b′), —R^(3b′)), —S(═O)₂—N(—R^(2b′), —R^(3b′)),—S(═O)₂—R^(2b′), —CF₃, —O—R^(2b′), —O—CH₂—CH₂—O—R^(2b′),—O—CH₂—C(═O)O—R^(2b′), —N(—R^(2b′))—CH₂—CH₂—O—R^(2b′),—N(—CH₂—CH₂—O—R^(2b′))₂,—N(R^(2b′))—C(═O)—R^(3b′)—N(R^(2b′))—S(═O)₂R^(3b′);

[0136] R^(2b′) and R^(3b′) are independently selected from the groupconsisting of:

[0137] —H, —C₁₋₄alkyl and —C₁₋₄alkyl-(carbocyclic aryl);

[0138] J is selected from the group consisting of:

[0139] a direct link, —S(═O)₂—, —C(═O)—, —N(—R⁷)—S(═O)₂—,—C(═O)—N(—R⁷)—S(═O)₂—, —C(═O)—N(—R⁷)—(CH₂)_(y)—, —S(═O)₂—N(—R⁷)—,—(CH₂)_(y)— and —N(—R⁷)—C(═O)—(CH₂)_(y)—;

[0140] y is an integer of 0-2;

[0141] R⁷is selected from the group consisting of:

[0142] —H, —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,—C₀₋₄alkyl-(carbocyclic aryl), —C₀₋₄alkyl-(heterocyclic ring system),—CH₂—C(═O)—O—C₁₋₄alkyl and —CH₂—C(═O)—O—C₁₋₄alkyl-(carbocyclic aryl);

[0143] X is selected from the group consisting of:

[0144] phenyl, which is substituted with 0-3 R^(1c) groups;

[0145] naphthyl, which is substituted with 0-3 R^(1c) groups;

[0146] a 6-membered heteroaromatic ring containing from 1-2 nitrogenatoms, wherein the ring is substituted with 0-3 R^(1c) groups; and

[0147] a fused heterobicyclic ring system, wherein the ring systemcontains 1-3 heteroatoms selected from N, O and S and is substitutedwith 0-3 R^(1c) groups;

[0148] R^(1c) is independently selected from the group consisting of:

[0149] halo, —C₁₋₄alkyl, —CN, —NO₂, —(CH₂)_(z)—N(—R^(2c), —R^(3c)),—C(═O)—N(—R^(2c), —R^(3c)), —C(═NH)—N(—R^(2c), —R^(3c)),—C(═NMe)—N(—R^(2c), —R^(3c)), —S(═O)₂—N(—R^(2c), —R^(3c)),—S(═O)₂—R^(2c), —S(═O)₂—O, —CF₃, —O—R^(2c), —O—CH₂CH₂—OR^(2c),—O—CH₂—C(═O)—O—R^(2c),—N(—R^(2c))—CH₂—CH₂—O—R^(2c)—N(—CH₂—CH₂—O—R^(2c))₂,—(CH₂),—N(—R^(2c))—C(═O)R^(3c), —(CH₂)_(z)—N(—R^(2c))—S(═O)₂—R^(3c), anda 5-6 membered heterocyclic ring containing 1-4 heteroatoms selectedfrom N, O and S;

[0150] z is an integer of 0-2;

[0151] R^(2c) and R^(3c) are independently selected from the groupconsisting of:

[0152] —H, —C₁₋₄alkyl and —C₁₋₄alkyl-(carbocyclic aryl);

[0153] and all pharmaceutically acceptable isomers, salts, hydrates,solvates and prodrug derivatives, thereof.

[0154] The present invention also provides compounds of the formula (I):

A-Q-D-E-G-J-X

[0155] wherein:

[0156] A is selected from the group consisting of:

[0157] Q is selected from the group consisting of:

[0158] a direct link, —C(═NH), —C(═NMe)—, —C(═O)—, —CH₂—, —NH—,—N(—CH₃)—, —O—, —NH—CH₂—, —CH₂—NH—, —N(—CH₃)—CH₂—, and —CH₂—N(—CH₃)—;

[0159] D is selected from the group consisting of:

[0160] E is selected from the group consisting of:

[0161] a direct link, —NH—C(═O)—, —N(—CH₃)—C(═O)—, —N(—CH₂CO₂H)—C(═O)—,—C(═O)—NH—, —C(═O)—N(—CH₃)—, —NH—CH₂— and —CH₂—NH—;

[0162] G is selected from the group consisting of:

[0163] R^(1b) is selected from the group consisting of:

[0164] —H, —Me, —CF₃, —F, —Cl, —Br, —SO₂Me, —CN, —CONH₂, —CONMe₂, —NH₂,—NO₂, —NHCOMe, —NHSO₂Me, —CH₂NH₂ and —CO₂H;

[0165] J is selected from the group consisting of:

[0166] a direct link, —NH—, —O—, —S(═O)₂—, —S(═O)₂—NH, —NH—S(═O)₂—,—C(═O)—, —NH—C(═O)— and —C(═O)—NH—;

[0167] X is selected from the group consisting of:

[0168] and all pharmaceutically acceptable isomers, salts, hydrates,solvates and prodrug derivatives, thereof.

[0169] The compounds listed in the following tables are an embodiment ofthe present invention: TABLE 1

[0170] wherein:

[0171] R^(1b) is selected from the group consisting of —H, —CH₃ and—CF₃. TABLE 2

[0172] wherein:

[0173] R^(1a1) and R^(1a2) are independently selected from the groupconsisting of —H, —F, —Cl and —Br;

[0174] R^(1b) is selected from the group consisting of —H, —CH₃ and CF₃;

[0175] R^(1c2) is selected from the group consisting of —H, —F, —Cl,—Br, —OH, —OCH₃ and —NH₂. TABLE 3

[0176] wherein:

[0177] R^(1b) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0178] R^(1c2) is selected from the group consisting of —H, —F, —Cl,—Br, —OH, —OCH₃ and —NH₂. TABLE 4

[0179] wherein:

[0180] R^(1a1) and R^(1a2) are independently selected from the groupconsisting of —H, —F, —Cl and —Br;

[0181] R^(1b) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0182] R^(1c1) is selected from the group consisting of —F, —Cl, —Br,—CN, —CH₂NH₂, —CH₂OH, —CONH₂, —C(═NH)NH₂, —CO₂H, —CO₂Me, —SO₂Me,—SO₂NH₂, —OH, —NH₂, and —NO₂. TABLE 5

[0183] wherein:

[0184] R^(1a1) and R^(1a2) are independently selected from the groupconsisting of —H, —F, —Cl and —Br,

[0185] R^(1b) is selected from the group consisting of —H, —CH₃ and—CF₃.

[0186] R^(1c3) is selected from the group consisting of —H, —F, —Cl,—Br, —OH, —OCH₃ and —NH₂. TABLE 6

[0187] wherein:

[0188] R^(1a1) and R^(1a2) are independently selected from the groupconsisting of —H, —F, —Cl and —Br;

[0189] R^(1b) is selected from the group consisting of —H, —CH₃, —CF₃,—CH₂CH₃, —CF₂CF₃, —CH₂NH₂, —CONH₂, —SO₂CH₃, —SO₂NH₂, —NH₂COCH₃ and—NH₂COCF₃;

[0190] R^(1c1) is selected from the group consisting of —H, —F, —Cl,—Br, —CN, —CH₂NH₂, —CH₂OH, —CONH₂, —C(═NH)NH₂, —CO₂H, —CO₂Me, —SO₂Me,—SO₂NH₂, —OH, —NH₂, and —NO₂;

[0191] R^(1c2) is selected from the group consisting of —H, —F, —Cl,—Br, —OH, —OCH₃, and —NH₂;

[0192] R^(1c3) is selected from the group consisting of —H, —F, —Cl,—Br, —OH, —OCH₃, and —NH₂. TABLE 7

[0193] wherein:

[0194] R¹ is selected from the group consisting of —H, —NH₂, —SO₂NH₂,—SO₂CH₃, —CN, —CONH₂, —CONH(CH₃)₂, —CON(CH₃)₂, —CH₂NH₂, CH₂NH(CH₃),—CH₂N(CH₃)₂;

[0195] R^(1i) is selected from the group consisting of —H, —NH₂,—SO₂NH₂, —SO₂CH₃, —CN, —CONH₂, —CONH(CH₃), —CON(CH₃)₂, —CH₂NH₂,CH₂NH(CH₃), —CH₂N(CH₃)₂;

[0196] R^(1a1) and R^(1a2) are independently selected from the groupconsisting of —H, —F, —Cl and —Br;

[0197] R^(1b) is selected from the group consisting of —H, —CH₃, —CF₃,—CH₂CH₃, —CF₂CF₃, —CH₂NH₂, —CONH₂, —SO₂CH₃, —SO₂NH₂, —NH₂COCH₃ and—NH₂COCF₃;

[0198] R^(1c1) is selected from the group consisting of —H, —F, —Cl,—Br, —CN, —CH₂NH₂, —CH₂OH, —CONH₂, —C(═NH)NH₂, —CO₂H, —CO₂Me, —SO₂Me,—SO₂NH₂, —OH, —NH₂, and —NO₂;

[0199] R^(1c2) is selected from the group consisting of —H, —F, —Cl,—Br, —OH, —OCH₃, and —NH₂;

[0200] R^(1c3) is selected from the group consisting of —H, —F, —Cl,—Br, —OH, —OCH₃, and —NH₂. TABLE 8

[0201] wherein:

[0202] R¹ is selected from the group consisting of —SO₂NH₂, —SO₂CH₃,—CN, —CONH₂, CONH(CH₃), —CON(CH₃)₂, —CH₂NH₂, —CH₂NH(CH₃), —CH₂N(CH₃)₂;

[0203] R^(1i) is selected from the group consisting of —H, —NH₂, —CONH₂,—CONH(CH₃), —CON(CH₃)₂, —CH₂NH₂, —CH₂NH(CH₃), —CH₂N(CH₃)₂;

[0204] R^(1b) is selected from the group consisting of —H, —CH₃ and—CF₃,

[0205] R^(1c1) is selected from the group consisting of —H, —F, —Cl,—Br, —CN, —CH₂NH₂, —CH₂OH, —CONH₂, —C(═NH)NH₂, —CO₂H, —CO₂Me, —SO₂Me,—SO₂NH₂, —OH, —NH₂, and —NO₂;

[0206] R^(1c2) is selected from the group consisting of —H, —F, —Cl,—Br, —OH, —OCH₃, and —NH₂,

[0207] R^(1c3) is selected from the group consisting of —H, —F, —Cl,—Br, —OH, —OCH₃, and —NH₂. TABLE 9

[0208] wherein:

[0209] A is selected from the group consisting of

[0210] R^(1a1) and R^(1a2) are independently selected from the groupconsisting of —H, —F, —Cl and —Br;

[0211] R^(1b) is selected from the group consisting of —H, —CH₃, —CF₃,—CH₂CH₃, —CF₂CF₃, —CH₂NH₂, —CONH₂, —SO₂CH₃, —SO₂NH₂, —NH₂COCH₃ and—NH₂COCF₃;

[0212] R^(1c1) is selected from the group consisting of —H, —F, —Cl,—Br, —CN, —CH₂NH₂, —CH₂OH, —CONH₂, —C(═NH)NH₂, —CO₂H, —CO₂Me, —SO₂Me,—SO₂NH₂, —OH, —NH₂, and —NO₂;

[0213] R^(1c2) is selected from the group consisting of —H, —F, —Cl,—Br, —OH, —OCH₃, and —NH₂;

[0214] R^(1c3) is selected from the group consisting of —H, —F, —Cl,—Br, —OH, —OCH₃, and —NH₂. TABLE 10

[0215] wherein:

[0216] A-Q is selected from the group consisting of:

[0217] R^(1a1) and R^(1a2) are independently selected from the groupconsisting of —H, —F, —Cl and —Br;

[0218] R^(1b) is selected from the group consisting of —H, —CH₃, —CF₃,—CH₂CH₃, —CF₂CF₃, —CH₂NH₂, —CONH₂, —SO₂CH₃, —SO₂NH₂, —NH₂COCH₃ and—NH₂COCF₃;

[0219] R^(1c1) is selected from the group consisting of —H, —F, —Cl,—Br, —CN, —CH₂NH₂, —CH₂OH, —CONH₂, —C(═NH)NH₂, —CO₂H, —CO₂Me, —SO₂Me,—SO₂NH₂, —OH, —NH₂, and —NO₂;

[0220] R^(1c2) is selected from the group consisting of —H, —F, —Cl,—Br, —OH, —OCH₃, and —NH₂;

[0221] R^(1c3) is selected from the group consisting of —H, —F, —Cl,—Br, —OH, —OCH₃, and —NH₂. TABLE 11

[0222] wherein:

[0223] R¹ is selected from the group consisting of —SO₂NH₂, —SO₂CH₃,—CN, —CONH₂, —CONH(CH₃), —CON(CH₃)₂, —CH₂NH₂, —CH₂NH(CH₃), —CH₂N(CH₃)₂;

[0224] R^(1a1) and R^(1a2) are independently selected from the groupconsisting of —H, —F, —Cl and —Br;

[0225] R^(1c1) is selected from the group consisting of —H, —F, —Cl,—Br, —CN, —CH₂NH₂, —CH₂OH, —CONH₂, —C(═NH)NH₂, —CO₂H, —CO₂Me, —SO₂Me,—SO₂NH₂, —OH, —NH₂, and —NO₂;

[0226] R^(1c2) is selected from the group consisting of —H, —F, —Cl,—Br, —OH, —OCH₃, and —NH₂;

[0227] R^(1c3) is selected from the group consisting of —H, —F, —Cl,—Br, —OH, —OCH₃, and —NH₂;

[0228] G is selected from the group consisting of:

[0229] wherein:

[0230] R^(1b1) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0231] R^(1b2) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0232] R^(1b3) is selected from the group consisting of —Cl, —NH₂, —CH₃and —CF₃ TABLE 12

[0233] wherein:

[0234] A is selected from the group consisting of:

[0235] R^(1a1) and R^(1a2) are independently selected from the groupconsisting of —H, —F, —Cl and —Br;

[0236] R^(1c1) is selected from the group consisting of —H, —F, —Cl,—Br, —CN, —CH₂NH₂, —CH₂OH, —CONH₂, —C(═NH)NH₂, —CO₂H, —CO₂Me, —SO₂Me,—SO₂NH₂, —OH, —NH₂, and —NO₂;

[0237] R^(1c2) is selected from the group consisting of —H, —F, —Cl,—Br, —OH, —OCH₃, and —NH₂,

[0238] R^(1c3) is selected from the group consisting of —H, —F, —Cl,—Br, —OH, —OCH₃, and —NH₂;

[0239] G is selected from the group consisting of:

[0240] wherein:

[0241] R^(1b1) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0242] R^(1b2) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0243] R^(1b3) is selected from the group consisting of —Cl, —NH₂, —CH₃and —CF₃. TABLE 13

[0244] wherein:

[0245] A-Q is selected from the group consisting of:

[0246] R^(1a1) and R^(1a2) are independently selected from the groupconsisting of —H, —F, —Cl and —Br;

[0247] R^(1c1) is selected from the group consisting of —H, —F, —Cl,—Br, —CN, —CH₂NH₂, —CH₂OH, —CONH₂, —C(NH)NH₂, —CO₂H, —CO₂Me, —SO₂Me,—SO₂NH₂, —OH, —NH₂, and —NO₂;

[0248] R^(1c2) is selected from the group consisting of —H, —F, —Cl,—Br, —OH, —OCH₃, and —NH₂;

[0249] R^(1c3) is selected from the group consisting of —H, —F, —Cl,—Br, —OH, —OCH₃, and —NH₂,

[0250] G is selected from the group consisting of:

[0251] wherein:

[0252] R^(1b1) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0253] R^(1b2) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0254] R^(1b3) is selected from the group consisting of —Cl, —NH₂, —CH₃and —CF₃. TABLE 14

[0255] wherein:

[0256] R¹ is selected from the group consisting of —SO₂NH₂, —SO₂CH₃,—CN, —CONH₂, —CONH(CH₃), —CON(CH₃)₂, —CH₂NH₂, —CH₂NH(CH₃), —CH₂N(CH₃)₂;

[0257] R^(1b) is selected from the group consisting of —H, —CH₃, —CF₃;

[0258] R^(1c1) is selected from the group consisting of —H, —F, —Cl,—Br, —CN, —CH₂NH₂, —CH₂OH, —CONH₂, —C(═NH)NH₂, —CO₂H, —CO₂Me, —SO₂Me,—SO₂NH₂, —OH, —NH₂; and —NO₂;

[0259] R^(1c2) is selected from the group consisting of —H, —F, —Cl,—Br, —OH, —OCH₃, and —NH₂;

[0260] R^(1c3) is selected from the group consisting of —H, —F, —Cl,—Br, —OH, —OCH₃, and —NH₂ TABLE 15

[0261] wherein:

[0262] A is selected from the group consisting of:

[0263] R^(1b) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0264] R^(1c1) is selected from the group consisting of —H, —F, —Cl,—Br, —CN, —CH₂NH₂, —CH₂OH, —CONH₂, —C(═NH)NH₂, —CO₂H, —CO₂Me, —SO₂Me,—SO₂NH₂, —OH, —NH₂, and —NO₂;

[0265] R^(1c2) is selected from the group consisting of —H, —F, —Cl,—Br, —OH, —OCH₃, and —NH₂;

[0266] R^(1c3) is selected from the group consisting of —H, —F, —Cl,—Br, —OH, —OCH₃, and —NH₂. TABLE 16

[0267] wherein:

[0268] A-Q is selected from the group consisting of:

[0269] R^(1b) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0270] R^(1c1) is selected from the group consisting of —H, —F, —Cl,—Br, —CN, —CH₂NH₂, —CH₂OH, —CONH₂, —C(NH)NH₂, —CO₂H, —CO₂Me, —SO₂Me,—SO₂NH₂, —OH, —NH₂, and —NO₂;

[0271] R^(1c2) is selected from the group consisting of —H, —F, —Cl,—Br, —OH, —OCH₃, and —NH₂;

[0272] R^(1c3) is selected from the group consisting of —H, —F, —Cl,—Br, —OH, —OCH₃, and —NH₂. TABLE 17

[0273] wherein:

[0274] R¹ is selected from the group consisting of —SO₂NH₂, —SO₂CH₃,—CN, —CONH₂, —CONH(CH₃), —CON(CH₃)₂, —CH₂NH₂, —CH₂NH(CH₃), —CH₂N(CH₃)₂;

[0275] R^(1a1) and R^(1a2) are independently selected from the groupconsisting of —H, —F, —Cl and Br;

[0276] R^(1b) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0277] R^(1c1) is selected from the group consisting of —H, —F, —Cl,—Br, —CN, —CH₂NH₂, —CH₂OH, —CONH₂, —C(═NH)NH₂, —CO₂H, —CO₂Me, —SO₂Me,—SO₂NH₂, —OH, —NH₂, and —NO₂;

[0278] R^(1c2) is selected from the group consisting of —H, —F, —Cl,—Br, —OH, —OCH₃, and —NH₂;

[0279] R^(1c3) is selected from the group consisting of —H, —F, —Cl,—Br, —OH, —OCH₃, and —NH₂. TABLE 18

[0280] wherein:

[0281] A is selected from the group consisting of:

[0282] R^(1a1) and R^(1a2) are independently selected from the groupconsisting of —H, —F, —Cl and Br;

[0283] R^(1b) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0284] R^(1c1) is selected from the group consisting of —H, —F, —Cl,—Br, —CN, —CH₂NH₂, —CH₂OH, —CONH₂, —C(═NH)NH₂, —CO₂H, —CO₂Me, —SO₂Me,—SO₂NH₂, —OH, —NH₂, and —NO₂;

[0285] R^(1c2) is selected from the group consisting of —H, —F, —Cl,—Br, —OH, —OCH₃, and —NH₂,

[0286] R^(1c3) is selected from the group consisting of —H, —F, —Cl,—Br, —OH, —OCH₃, and —NH₂. TABLE 19

[0287] wherein:

[0288] A-Q is selected from the group consisting of:

[0289] R^(1a1) and R^(1a2) are independently selected from the groupconsisting of —H, —F, —Cl and Br,

[0290] R^(1b) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0291] R^(1c1) is selected from the group consisting of —H, —F, —Cl,—Br, —CN, —CH₂NH₂, —CH₂OH, —CONH₂, —C(═NH)NH₂, —CO₂H, —CO₂Me, —SO₂Me,—SO₂NH₂, —OH, —NH₂, and —NO₂;

[0292] R^(1c2) is selected from the group consisting of —H, —F, —Cl,—Br, —OH, —OCH₃, and —NH₂,

[0293] R^(1c3) is selected from the group consisting of —H, —F, —Cl,—Br, —OH, —OCH₃, and —NH₂. TABLE 20

[0294] wherein:

[0295] R¹ is selected from the group consisting of —SO₂NH₂, —SO₂CH₃,—CN, —CONH₂, —CONH(CH₃), —CON(CH₃)₂, —CH₂NH₂, —CH₂NH(CH₃), —CH₂N(CH₃)₂;

[0296] R^(1a1) and R^(1a2) are independently selected from the groupconsisting of —H, —F, —Cl and —Br;

[0297] R^(1c1) is selected from the group consisting of —H, —F, —Cl,—Br, —CN, —CH₂NH₂, —CH₂OH, —CONH₂, —C(═NH)NH₂, —CO₂H, —CO₂Me, —SO₂Me,—SO₂NH₂, —OH, —NH₂, and —NO₂;

[0298] R^(1c2) is selected from the group consisting of —H, —F, —Cl,—Br, and —OCH₃;

[0299] R^(1c3) is selected from the group consisting of —H, —F, —Cl,—Br, —OH, —OCH₃, —NH₂, —CONH₂, —CH₂NH₂, —CH₂NHCH₃, —CH₂N(CH₃)₂,—C(═NH)NH₂;

[0300] G is selected from the group consisting of:

[0301] wherein:

[0302] R^(1b1) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0303] R^(1b2) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0304] R^(1b3) is selected from the group consisting of —Cl, —NH₂, —CH₃and —CF₃. TABLE 21

[0305] wherein:

[0306] R¹ is selected from the group consisting of —SO₂NH₂, —SO₂CH₃,—CN, —CONH₂, —CONH(CH₃), —CON(CH₃)₂, —CH₂NH₂, —CH₂NH(CH₃), —CH₂N(CH₃)₂;

[0307] R^(1a1) and R^(1a2) are independently selected from the groupconsisting of —H, —F, —Cl and —Br;

[0308] R^(1c1) is selected from the group consisting of —H, —F, —Cl,—Br, —CN, —CH₂NH₂, —CH₂OH, —CONH₂, —C(═NH)NH₂, —CO₂H, —CO₂Me, —SO₂Me,—SO₂NH₂, —OH, —NH₂, and —NO₂;

[0309] R^(1c2) is selected from the group consisting of —CH₂—, —O—,—NH—, —N(CH₃)—, —CH₂CH₂—, —O—CH₂—, —NH—CH₂—, and —N(CH₃)—CH₂—;

[0310] R^(1c3) is selected from the group consisting of —CH₂—, —O—,—NH—, —N(CH₃)—, and —CH(NH₂)—;

[0311] G is selected from the group consisting of:

[0312] wherein:

[0313] R^(1b1) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0314] R^(1b2) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0315] R^(1b3) is selected from the group consisting of —Cl, —NH₂, —CH₃and —CF₃. TABLE 22

[0316] wherein:

[0317] R¹ is selected from the group consisting of —SO₂NH₂, —SO₂CH₃,—CN, —CONH₂, —CONH(CH₃), —CON(CH₃)₂, —CH₂NH₂, —CH₂NH(CH₃), —CH₂N(CH₃)₂;

[0318] R^(1a1) and R^(1a2) are independently selected from the groupconsisting of —H, —F, —Cl and —Br;

[0319] R^(1c1) is selected from the group consisting of —H, —F, —Cl,—Br, —CN, —CH₂NH₂, —CH₂O H, —CONH₂, —C(═NH)NH₂, —CO₂H, —CO₂Me, —SO₂Me,—SO₂NH₂, —OH, —NH₂, and —NO₂;

[0320] R^(1c2) is selected from the group consisting of —H, —F, —Cl,—Br, and —OCH₃;

[0321] R^(1c3) is selected from the group consisting of —H, —F, —Cl,—Br, —OH, —OCH₃, —NH₂, —CONH₂, —CH₂NH₂, —CH₂NHCH₃, —CH₂N(CH₃)₂,—C(═NH)NH₂;

[0322] G is selected from the group consisting of:

[0323] Wherein:

[0324] R^(1b1) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0325] R^(1b2) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0326] R^(1b3) is selected from the group consisting of —Cl, —NH₂, —CH₃and —CF₃. TABLE 23

[0327] wherein:

[0328] R¹ is selected from the group consisting of —SO₂NH₂, —SO₂CH₃,—CN, —CONH₂, —CONH(CH₃), —CON(CH₃)₂, —CH₂NH₂, —CH₂NH(CH₃), —CH₂N(CH₃)₂;

[0329] R^(1a1) and R^(1a2) are independently selected from the groupconsisting of —H, —F, —Cl and —Br;

[0330] R^(1c1) is selected from the group consisting of —H, —F, —Cl,—Br, —CN, —CH₂NH₂, —CH₂OH, —CONH₂, —C(═NH)NH₂, —CO₂H, —CO₂Me, —SO₂Me,—SO₂NH₂, —OH, —NH₂, and —NO₂;

[0331] R^(1c2) is selected from the group consisting of —H, —F, —Cl,—Br, and —OCH₃;

[0332] G is selected from the group consisting of:

[0333] wherein:

[0334] R^(1b1) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0335] R^(1b2) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0336] R^(1b3) is selected from the group consisting of —Cl, —NH₂, —CH₃and —CF₃. TABLE 24

[0337] wherein:

[0338] R¹ is selected from the group consisting of —SO₂NH₂, —SO₂CH₃,—CN, —CONH₂, —CONH(CH₃), —CON(CH₃)₂, —CH₂NH₂, —CH₂NH(CH₃), —CH₂N(CH₃)₂;

[0339] R^(1a1) and R^(1a2) are independently selected from the groupconsisting of —H, —F, —Cl and —Br;

[0340] R^(1c1) is selected from the group consisting of —H, —F, —Cl,—Br, —CN, —CH₂NH₂, —CH₂OH, —CONH₂, —C(═NH)NH₂, —CO₂H, —CO₂Me, —SO₂Me,—SO₂NH₂, —OH, —NH₂, and —NO₂;

[0341] R^(1c2) is selected from the group consisting of —CH—, and —N—;

[0342] R^(1c3) is selected from the group consisting of —NH—, and —O—;

[0343] G is selected from the group consisting of:

[0344] wherein:

[0345] R^(1b1) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0346] R^(1b2) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0347] R^(1b3) is selected from the group consisting of —Cl, —NH₂, —CH₃and —CF₃. TABLE 25

[0348] wherein.

[0349] R¹ is selected from the group consisting of —SO₂NH₂, —SO₂CH₃,—CN, —CONH₂, —CONH(CH₃), —CON(CH₃)₂, —CH₂NH₂, —CH₂NH(CH₃), —CH₂N(CH₃)₂;

[0350] R^(1a1) and R^(1a2) are independently selected from the groupconsisting of —H, —F, —Cl and —Br;

[0351] R^(1c1) is selected from the group consisting of —H, —F, —Cl,—Br, —CN, —CH₂NH₂, —CH₂OH, —CONH₂, —C(═NH)NH₂, —CO₂H, —CO₂Me, —SO₂Me,—SO₂NH₂, —OH, —NH₂, and —NO₂;

[0352] R^(1c2) is selected from the group consisting of —CH₂—, —O— and—NH—;

[0353] R^(1c3) is selected from the group consisting of —CH—, —C(NH₂)—and —N—;

[0354] G is selected from the group consisting of:

[0355] wherein:

[0356] R^(1b1) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0357] R^(1b2) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0358] R^(1b3) is selected from the group consisting of —Cl, —NH₂, —CH₃and —CF₃. TABLE 26

[0359] wherein:

[0360] A is selected from the group consisting of:

[0361] R^(1a1) and R^(1a2) are independently selected from the groupconsisting of —H, —F, —Cl and —Br;

[0362] R^(1c1) is selected from the group consisting of —H, —F, —Cl,—Br, —CN, —CH₂NH₂, —CH₂OH, —CONH₂, —C(═NH)NH₂, —CO₂H, —CO₂Me, —SO₂Me,—SO₂NH₂, —OH, —NH₂, and —NO₂;

[0363] R^(1c2) is selected from the group consisting of —H, —F, —Cl,—Br, and —OCH₃;

[0364] R^(1c3) is selected from the group consisting of —H, —F, —Cl,—Br, —OH, —OCH₃, —NH₂, —CONH₂, —CH₂NH₂, —CH₂NHCH₃, —CH₂N(CH₃)₂,—C(═NH)NH₂;

[0365] G is selected from the group consisting of:

[0366] wherein:

[0367] R^(1b1) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0368] R^(1b2) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0369] R^(1b3) is selected from the group consisting of —Cl, —NH₂, —CH₃and —CF₃. TABLE 27

[0370] wherein:

[0371] A-Q is selected from the group consisting of:

[0372] R^(1a1) and R^(1a2) are independently selected from the groupconsisting of —H, —F, —Cl and —Br;

[0373] R^(1c1) is selected from the group consisting of —H, —F, —Cl,—Br, —CN, —CH₂NH₂, —CH₂OH, —CONH₂, —C(═NH)NH₂, —CO₂H, —CO₂Me, —SO₂Me,—SO₂NH₂, —OH, —NH₂, and —NO₂;

[0374] R^(1c2) is selected from the group consisting of —H, —F, —Cl,—Br, and —OCH₃;

[0375] R^(1c3) is selected from the group consisting of —H, —F, —Cl,—Br, and -O CH3, —NH₂, —CONH₂, —CH₂NH₂, —CH₂NHCH₃, —CH₂N(CH₃)₂,—C(═NH)NH₂;

[0376] G is selected from the group consisting of:

[0377] wherein:

[0378] R^(1b1) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0379] R^(1b2) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0380] R^(1b3) is selected from the group consisting of —Cl, —NH₂, —CH₃and —CF₃. TABLE 28

[0381] wherein:

[0382] A is selected from the group consisting of:

[0383] R^(1a1) and R^(1a2) are independently selected from the groupconsisting of —H, —F, —Cl and —Br;

[0384] R^(1c1) is selected from the group consisting of —H, —F, —Cl,—Br, —CN, —CH₂NH₂, —CH₂OH, —CONH₂, —C(═NH)NH₂, —CO₂H, —CO₂Me, —SO₂Me,—SO₂NH₂, —OH, —NH₂, and —NO₂;

[0385] R^(1c2) is selected from the group consisting of —H, —F, —Cl,—Br, and —OCH₃;

[0386] R^(1c3) is selected from the group consisting of —H, —F, —Cl,—Br, —OH, —OCH₃, —NH₂, —CONH₂, —CH₂NH₂, —CH₂NHCH₃, —CH₂N(CH₃)₂,—C(═NH)NH₂;

[0387] G is selected from the group consisting of:

[0388] wherein:

[0389] R^(1b1) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0390] R^(1b2) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0391] R^(1b3) is selected from the group consisting of —Cl, —NH₂, —CH₃and —CF₃ TABLE 29

[0392] wherein:

[0393] A-Q is selected from the group consisting of:

[0394] R^(1a1) and R^(1a2) are idpnetyselected from the group consistingof —H, —F, —Cl and —Br;

[0395] R^(1c1) is selected from the group consisting of —H, —F, —Cl,—Br, —CN, —CH₂NH₂, —CH₂OH, —CONH₂, —C(═NH)NH₂, —CO₂H, —CO₂Me, —SO₂Me,—SO₂NH₂, —OH, —NH₂, and —NO₂;

[0396] R^(1c2) is selected from the group consisting of —CH₂—, —O—,—NH—, —N(CH₃)—, —CH₂CH₂—, —O—CH₂—, —NH—CH₂—, and —N(CH₃)—CH₂—;

[0397] R^(1c3) is selected from the group consisting of —CH₂—, —O—,—NH—, —N(CH₃)—, and —CH(NH₂)—.

[0398] G is selected from the group consisting of:

[0399] wherein:

[0400] R^(1b1) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0401] R^(1b2) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0402] R^(1b3) is selected from the group consisting of —Cl, —NH₂, —CH₃and —CF₃. TABLE 30

[0403] wherein:

[0404] A is selected from the group consisting of

[0405] R^(1a1) and R^(1a2) are independently selected from the groupconsisting of —H, —F, —Cl and —Br;

[0406] R^(1c1) is selected from the group consisting of —H, —F, —Cl,—Br, —CN, —CH₂NH₂,—CH₂OH, —CONH₂, —C(═NH)NH₂, —CO₂H, —CO₂Me, —SO₂Me,—SO₂NH₂, —OH, —NH₂, and —NO₂;

[0407] R^(1c2) is selected from the group consisting of —H, —F, —Cl,—Br, and —OCH₃;

[0408] R^(1c3) is selected from the group consisting of —H, —F, —Cl,—Br, —OH, —OCH₃, —NH₂, —CONH₂, —CH₂NH₂, —CH₂NHCH₃, —CH₂N(CH₃)₂,—C(═NH)NH₂, —C(═NH)NH(CH₃), —C(═NH)NH(CH₃)₂;

[0409] G is selected from the group consisting of:

[0410] wherein:

[0411] R^(1b1) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0412] R^(1b2) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0413] R^(1b3) is selected from the group consisting of —Cl, —NH₂, —CH₃and —CF₃. TABLE 31

[0414] wherein:

[0415] A-Q is selected from the group consisting of:

[0416] R^(1a1) and R^(1a2) are independently selected from the groupconsisting of —H, —F, —Cl and —Br;

[0417] R^(1c1) is selected from the group consisting of —H, —F, —Cl,—Br, —CN, —CH₂NH₂, —CH₂O H, —CONH₂, —C(═NH)NH₂, —CO₂H, —CO₂Me, —SO₂Me,—SO₂NH₂, —OH, —NH₂, and —NO₂;

[0418] R^(1c2) is selected from the group consisting of —H, —F, —Cl,—Br, —OH, —OCH₃, and —NH₂;

[0419] R^(1c3) is selected from the group consisting of —H, —F, —Cl,—Br, —OH, —OCH₃, and —NH₂;

[0420] G is selected from the group consisting of:

[0421] wherein:

[0422] R^(1b1) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0423] R^(1b2) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0424] R^(1b3) is selected from the group consisting of —Cl, —NH₂, —CH₃and —CF₃. TABLE 32

[0425] wherein:

[0426] A is selected from the group consisting of:

[0427] R^(1a1) and R^(1a2) are independently selected from the groupconsisting of —H, —F, —Cl and —Br;

[0428] R^(1c1) is selected from the group consisting of —H, —F, —Cl,—Br, —CN, —CH₂NH₂, —CH₂OH, —CONH₂, —C(═NH)NH₂, —CO₂H, —CO₂Me, —SO₂Me,—SO₂NH₂, —OH, —NH₂, and —NO₂;

[0429] R^(1c2) is selected from the group consisting of —H, —F, —Cl,—Br, and —OCH₃;

[0430] G is selected from the group consisting of:

[0431] wherein:

[0432] R^(1b1) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0433] R^(1b2) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0434] R^(1b3) is selected from the group consisting of —Cl, —NH₂, —CH₃and —CF₃. TABLE 33

[0435] wherein:

[0436] A is selected from the group consisting of:

[0437] R^(1a1) and R^(1a2) are independently selected from the groupconsisting of —H, —F, —Cl and —Br;

[0438] R^(1c1) is selected from the group consisting of —H, —F, —Cl,—Br, —CN, —CH₂NH₂, —CH₂O H, —CONH₂, —C(═NH)NH₂, —CO₂H, —CO₂Me, —SO₂Me,—SO₂NH₂, —OH, —NH₂, and —NO₂;

[0439] R^(1c2) is selected from the group consisting of —H, —F, —Cl,—Br, and —OCH₃;

[0440] G is selected from the group consisting of:

[0441] wherein:

[0442] R^(1b1) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0443] R^(1b2) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0444] R^(1b3) is selected from the group consisting of —Cl, —NH₂, —CH₃and —CF₃. TABLE 34

[0445] wherein:

[0446] A-Q is selected from the group consisting of:

[0447] R^(1a1) and R^(1a2) are independently selected from the groupconsisting of —H, —F, —Cl and —Br;

[0448] R^(1c1) is selected from the group consisting of —H, —F, —Cl,—Br, —CN, —CH₂NH₂, —CH₂OH, —CONH₂, —C(═NH)NH₂, —CO₂H, —CO₂Me, —SO₂Me,—SO₂NH₂, —OH, —NH₂, and —NO₂;

[0449] R^(1c2) is selected from the group consisting of —H, —F, —Cl,—Br, and —OCH₃;

[0450] G is selected from the group consisting of:

[0451] wherein:

[0452] R^(1b1) is selected from the group consisting of —H, —CH₃ and—CF₃;,

[0453] R^(1b2) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0454] R^(1b3) is selected from the group consisting of —Cl, —NH₂, —CH₃and —CF₃. TABLE 35

[0455] wherein:

[0456] A-Q is selected from the group consisting of:

[0457] wherein:

[0458] A is selected from the group consisting of:

[0459] R^(1a1) and R^(1a2) are independently selected from the groupconsisting of —H, —F, —Cl and —Br;

[0460] R^(1c1) is selected from the group consisting of —H, —F, —Cl,—Br, —CN, —CH₂NH₂, —CH₂OH, —CONH₂, —C(═NH)NH₂, —CO₂H, —CO₂Me, —SO₂Me,—SO₂NH₂, —OH, —NH₂, and —NO₂;

[0461] R^(1c2) is selected from the group consisting of —H, —F, —Cl,—Br, and —OCH₃;

[0462] G is selected from the group consisting of:

[0463] wherein:

[0464] R^(1b1) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0465] R^(1b2) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0466] R^(1b3) is selected from the group consisting of —Cl, —NH₂, —CH₃and —CF₃. TABLE 36

[0467] wherein:

[0468] A-Q is selected from the group consisting of:

[0469] wherein:

[0470] A is selected from the group consisting of:

[0471] R^(1a1) and R^(1a2) are independently selected from the groupconsisting of —H, —F, —Cl and —Br;

[0472] R^(1c1) is selected from the group consisting of —H, —F, —Cl,—Br, —CN, —CH₂NH₂, —CH₂OH, —CONH₂, —C(═NH)NH₂, —CO₂H, —CO₂Me, —SO₂Me,—SO₂NH₂, —OH, —NH₂, and —NO₂;

[0473] R^(1c2) is selected from the group consisting of —CH₂—, —O— and—NH—;

[0474] R^(1c3) is selected from the group consisting of —CH—, —C(NH₂)—and —N—;

[0475] G is selected from the group consisting of

[0476] wherein:

[0477] R^(1b1) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0478] R^(1b2) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0479] R^(1b3) is selected from the group consisting of —Cl, —NH₂, —CH₃and —CF₃. TABLE 37

[0480] wherein:

[0481] R¹ is selected from the group consisting of —SO₂NH₂, —SO₂CH₃,—CN, —CONH₂, —CONH(CH₃), —CON(CH₃)₂, —CH₂NH₂, —CH₂NH(CH₃), —CH₂N(CH₃)₂;

[0482] R^(1a) is selected from the group consisting of —H, —F, —Cl and—Br;

[0483] R^(1b1) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0484] R^(1b2) is selected from the group consisting of —Cl, —NH₂, —CH₃and —CF₃;

[0485] R^(1c1) is selected from the group consisting of —H, —F, —Cl,—Br, —CN, —CH₂NH₂, —CH₂OH, —CONH₂, —C(═NH)NH₂, —CO₂H, —CO₂Me, —SO₂Me,—SO₂NH₂, —OH, —NH₂, and —NO₂;

[0486] R^(1c2) is selected from the group consisting of —H, —F, —Cl and—Br;

[0487] R^(1c3) is selected from the group consisting of —H, —F, —Cl and—Br. TABLE 38

[0488] wherein:

[0489] R¹ is selected from the group consisting of —SO₂NH₂, —SO₂CH₃,—CN, —CONH₂, CONH(CH₃), —CON(CH₃)₂, —CH₂NH₂, —CH₂NH(CH₃), —CH₂N(CH₃)₂;

[0490] R^(1a) is selected from the group consisting of —H, —F, —Cl and—Br;

[0491] R^(1b1) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0492] R^(1b2) is selected from the group consisting of —Cl, —NH₂, —CH₃and —CF₃;

[0493] R^(1c1) is selected from the group consisting of —H, —F, —Cl,—Br, —CN, —CH₂NH₂, —CH₂OH, —CONH₂, —C(═NH)NH₂, —CO₂H, —CO₂Me, —SO₂Me,—SO₂NH₂, —OH, —NH₂, and —NO₂;

[0494] R^(1c2) is selected from the group consisting of —H, —F, —Cl and—Br;

[0495] R^(1c3) is selected from the group consisting of —H and —NH₂.TABLE 39

[0496] wherein:

[0497] A-Q is selected from the group consisting of:

[0498] wherein:

[0499] A is selected from the group consisting of:

[0500] R^(1a) is selected from the group consisting of —H, —F, —Cl and—Br;

[0501] R^(1b1) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0502] R^(1b2) is selected from the group consisting of —Cl, —NH₂, —CH₃and —CF₃;

[0503] R^(1c1) is selected from the group consisting of —H, —F, —Cl,—Br, —CN, —CH₂NH₂, —CH₂OH, —CONH₂, —C(═NH)NH₂, —CO₂H, —CO₂Me, —SO₂Me,—SO₂NH₂, —OH, —NH₂, and —NO₂;

[0504] R^(1c2) is selected from the group consisting of —H, —F, —Cl and—Br;

[0505] R^(1c3) is selected from the group consisting of —H, —F, —Cl and—Br. TABLE 40

[0506] wherein:

[0507] A-Q is selected from the group consisting of:

[0508] wherein:

[0509] A is selected from the group consisting of:

[0510] R^(1a) is selected from the group consisting of —H, —F, —Cl and—Br;

[0511] R^(1b1) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0512] R^(1b2) is selected from the group consisting of —Cl, —NH₂, —CH₃and —CF₃;

[0513] R^(1c1) is selected from the group consisting of —H, —F, —Cl,—Br, —CN, —CH₂NH₂, —CH₂OH, —CONH₂, —C(═NH)NH₂, —CO₂H, —CO₂Me, —SO₂Me,—SO₂NH₂, —OH, —NH₂, and —NO₂;

[0514] R^(1c2) is selected from the group consisting of —H, —F, —Cl and—Br;

[0515] R^(1c3) is selected from the group consisting of —H and —NH₂.TABLE 41

[0516] wherein:

[0517] R¹ is selected from the group consisting of —SO₂NH₂, —SO₂CH₃,—CN, —CONH₂, —CONH(CH₃), —CON(CH₃)₂, —CH₂NH₂, —CH₂NH(CH₃), —CH₂N(CH₃)₂;

[0518] R^(1a) is selected from the group consisting of —H, —F, —Cl and—Br;

[0519] R^(1b1) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0520] R^(1b2) is selected from the group consisting of —Cl, —NH₂, —CH₃and —CF₃;

[0521] R^(1c1) is selected from the group consisting of —H, —F, —CN,—CH₂NH₂, —CONH₂, —SO₂Me, —SO₂NH₂ and —NO₂;

[0522] R^(1c2) is selected from the group consisting of —H, —F, —Cl, —Brand —OCH₃;

[0523] R^(1c3) is selected from the group consisting of —H, —F, —Cl, Br,—OCH₃, —CH₂NH₂, —CONH₂ and —C(N═H)NH₂. TABLE 42

[0524] wherein:

[0525] R¹ is selected from the group consisting of —SO₂NH₂, —SO₂CH₃, CN,—CONH₂, —CONH(CH₃), —CON(CH₃)₂, —CH₂NH₂, —CH₂NH(CH₃), —CH₂N(CH₃)₂;

[0526] R^(1a) is selected from the group consisting of —H, —F, —Cl and—Br;

[0527] R^(1b1) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0528] R^(1b2) is selected from the group consisting of —Cl, —NH₂, —CH₃and —CF₃;

[0529] R^(1c1) is selected from the group consisting of —H, —F, —CN,—CH₂NH₂, —CONH₂, —SO₂Me, —SO₂NH₂ and —NO₂;

[0530] R^(1c2) is selected from the group consisting of —H, —F, —Cl, —Brand —OCH₃;

[0531] R^(1c3) is selected from the group consisting of —H, —F, —Cl, Br,—OCH₃, —CH₂NH₂, —CONH₂ and —C(N═H)NH₂. TABLE 43

[0532] wherein:

[0533] A-Q is selected from the group consisting of:

[0534] wherein:

[0535] A is selected from the group consisting of:

[0536] wherein:

[0537] R^(1a) is selected from the group consisting of —H, —F, —Cl and—Br;

[0538] R^(1b1) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0539] R^(1b2) is selected from the group consisting of —Cl, —NH₂, —CH₃and —CF₃;

[0540] R^(1c1) is selected from the group consisting of —H, —F, —CN,—CH₂NH₂, —CONH₂, —SO₂Me, —SO₂NH₂ and —NO₂.

[0541] R^(1c2) is selected from the group consisting of —H, —F, —Cl, —Brand —OCH₃;

[0542] R^(1c3) is selected from the group consisting of —H, —F, —Cl, Br,—OCH₃, —CH₂NH₂, —CONH₂ and —C(N═H)NH₂. TABLE 44

[0543] wherein:

[0544] A-Q is selected from the group consisting of:

[0545] wherein:

[0546] A is selected from the group consisting of:

[0547] wherein:

[0548] R^(1a) is selected from the group consisting of —H, —F, —Cl and—Br;

[0549] R^(1b1) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0550] R^(1b2) is selected from the group consisting of —Cl, —NH₂, —CH₃and —CF₃;

[0551] R^(1c1) is selected from the group consisting of —H, —F, —CN,—CH₂NH₂, —CONH₂, —SO₂Me, —SO₂NH₂ and —NO₂;

[0552] R^(1c2) is selected from the group consisting of —H, —F, —Cl, —Brand —OCH₃;

[0553] R^(1c3) is selected from the group consisting of —H, —F, —Cl, Br,—OCH₃, —CH₂NH₂, —CONH₂ and —C(N═H)NH₂. TABLE 45

[0554] wherein:

[0555] R¹ is selected from the group consisting of —SO₂NH₂, —SO₂CH₃,—CN, —CONH₂, —CONH(CH₃), —CON(CH₃)₂, —CH₂NH₂, —CH₂NH(CH₃), —CH₂N(CH₃)₂;

[0556] R^(1a1) and R^(1a2) are independently selected from the groupconsisting of —H, —F, —Cl and —Br;

[0557] R^(1c2) and R^(1c3) are independently selected from the groupconsisting of —H, —F, —Cl, —Br, and —OCH₃;

[0558] G is selected from the group consisting of:

[0559] wherein:

[0560] R^(1b1) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0561] R^(1b2) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0562] R^(1b3) is selected from the group consisting of —Cl, —NH₂, —CH₃and,—CF₃. TABLE 46

[0563] wherein:

[0564] R¹ is selected from the group consisting of —SO₂NH₂, —SO₂CH₃,—CN, —CONH₂, —CONH(CH₃), —CON(CH₃)₂, —CH₂NH₂, —CH₂NH(CH₃), —CH₂N(CH₃)₂;

[0565] R^(1a1) and R^(1a2) are independently selected from the groupconsisting of —H, —F, —Cl and —Br;

[0566] R^(1c2) and R^(1c3) are independently selected from the groupconsisting of —H, —F, —Cl, —Br, and —OCH₃;

[0567] G is selected from the group consisting of:

[0568] wherein:

[0569] R^(1b1) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0570] R^(1b2) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0571] R^(1b3) is selected from the group consisting of —Cl, —NH₂, —CH₃and —CF₃. TABLE 47

[0572] wherein:

[0573] A-Q is selected from the group consisting of:

[0574] wherein:

[0575] A is selected from the group consisting of:

[0576] R^(1a1) and R^(1a2) are independently selected from the groupconsisting of —H, —F, —Cl and —Br;

[0577] R^(1c2) and R^(1c3) are independently selected from the groupconsisting of —H, —F, —Cl, —Br, and —OCH₃;

[0578] G is selected from the group consisting of:

[0579] wherein:

[0580] R^(1b1) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0581] R^(1b2) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0582] R^(1b3) is selected from the group consisting of —Cl, —NH₂, —CH₃and —CF₃. TABLE 48

[0583] wherein:

[0584] A-Q is selected from the group consisting of:

[0585] wherein:

[0586] A is selected from the group consisting of:

[0587] R^(1a1) and R^(1a2) are independently selected from the groupconsisting of —H, —F, —Cl and —Br;

[0588] R^(1c2) and R^(1c3) are independently selected from the groupconsisting of —H, —F, —Cl, —Br, and —OCH₃;

[0589] G is selected from the group consisting of:

[0590] wherein:

[0591] R^(1b1) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0592] R^(1b2) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0593] R^(1b3) is selected from the group consisting of —Cl, —NH₂, —CH₃and —CF₃. TABLE 49

[0594] wherein:

[0595] A-Q is selected from the group consisting of:

[0596] wherein:

[0597] A is selected from the group consisting of:

[0598] R^(1a1) and R^(1a2) are independently selected from the groupconsisting of —H, —F, —Cl and —Br;

[0599] R^(1c2) and R^(1c3) are independently selected from the groupconsisting of —H, —F, —Cl, —Br, and —OCH₃;

[0600] G is selected from the group consisting of:

[0601] wherein:

[0602] R^(1b1) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0603] R^(1b2) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0604] R^(1b3) is selected from the group consisting of —Cl, —NH₂, —CH₃and —CF₃. TABLE 50

[0605] wherein:

[0606] R¹ is selected from the group consisting of —SO₂NH₂, —SO₂CH₃,—CN, —CONH₂, —CONH(CH₃), —CON(CH₃)₂, —CH₂NH₂, —CH₂NH(CH₃), —CH₂N(CH₃)₂;

[0607] R^(1a) is selected from the group consisting of —H, —F, —Cl and—Br;

[0608] R^(1b1) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0609] R^(1c2) and R^(1c3) are independently selected from the groupconsisting of —H, —F, —Cl, —Br, and —OCH₃. TABLE 51

[0610] wherein:

[0611] R¹ is selected from the group consisting of —SO₂NH₂, —SO₂CH₃,—CN, —CONH₂, —CONH(CH₃), —CON(CH₃)₂, —CH₂NH₂, —CH₂NH(CH₃), —CH₂N(CH₃)₂;

[0612] R^(1a) is selected from the group consisting of —H, —F, —Cl and—Br;

[0613] R^(1b1) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0614] R^(1c2) and R^(1c3) are independently selected from the groupconsisting of —H, —F, —Cl, —Br, and —OCH₃. TABLE 52

[0615] wherein:

[0616] A-Q is selected from the group consisting of:

[0617] wherein:

[0618] A is selected from the group consisting of:

[0619] R^(1a) is selected from the group consisting of —H, —F, —Cl and—Br;

[0620] R^(1b1) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0621] R^(1c2) and R^(1c3) are independently selected from the groupconsisting of —H, —F, —Cl, —Br and —OCH₃. TABLE 53

[0622] wherein:

[0623] A-Q is selected from the group consisting of:

[0624] wherein:

[0625] A is selected from the group consisting of:

[0626] R^(1a) is selected from the group consisting of —H, —F, —Cl and—Br;

[0627] R^(1b1) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0628] R^(1c2) and R^(1c3) are independently selected from the groupconsisting of —H, —F, —Cl, —Br and —OCH₃.

[0629] The following compounds are an embodiment of the presentinvention:

[0630] wherein:

[0631] R¹ is selected from the group consisting of:

[0632] —SO₂NH₂, —SO₂Me, —CH₂NH₂ and —CH₂NMe₂;

[0633] R^(1a) is selected from the group consisting of:

[0634] —H, —F, —Cl and —Br,

[0635] R^(1c1) is selected from the group consisting of:

[0636] —H, —F, —Cl, —Br, —NH₂, —OH, —SO₂Me, —SO₂Et, —SO₂NH₂, —NO₂,—CH₂NH₂, —CN, —CONH₂, —CH₂OH;

[0637] R^(1c2) is selected from the group consisting of:

[0638] —H, —F, —Cl and —Br;

[0639] R^(1c3) is selected from the group consisting of:

[0640] —H, —F, —Cl and —Br;

[0641] G is selected from the group consisting of:

[0642] wherein:

[0643] R^(1b1) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0644] R^(1b2) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0645] R^(1b3) is selected from the group consisting of —Cl, —NH₂, —CH₃and —CF₃.

[0646] The following compounds are an embodiment of the presentinvention:

[0647] wherein:

[0648] R¹ is selected from the group consisting of:

[0649] —SO₂NH₂, —SO₂Me, —CH₂NH₂ and —CH₂NMe₂;

[0650] R^(1a) is selected from the group consisting of:

[0651] —H, —F, —Cl and —Br;

[0652] R^(1c1) is selected from the group consisting of:

[0653] —H, —F, —Cl, —Br, —NH₂, —OH, —SO₂Me, —SO₂Et, —SO₂NH₂, —NO₂,—CH₂NH₂, —CN, —CONFH₂, —CH₂OH;

[0654] R^(1c2) is selected from the group consisting of:

[0655] —H, —F, —Cl, —Br and —OMe;

[0656] R^(1c3) is selected from the group consisting of:

[0657] —H, —F, —Cl, —Br, —OCH₃, —NH₂, —CH₂NH₂, —CONH₂, —CONHMe, —CONMe₂

[0658] G is selected from the group consisting of:

[0659] wherein:

[0660] R^(1b1) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0661] R^(1b2) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0662] R^(1b3) is selected from the group consisting of —Cl, —NH₂, —CH₃and —CF₃.

[0663] The following compounds are an embodiment of the presentinvention:

[0664] wherein:

[0665] R¹ is selected from the group consisting of:

[0666] —SO₂NH₂, —SO₂CH₃, —CN, —CONH₂, —CONH(CH₃), —CON(CH₃)₂, —CH₂NH₂,—CH₂NH(CH₃), —CH₂N(CH₃)₂;

[0667] R^(1a) is selected from the group consisting of:

[0668] —H, —F, —Cl and —Br;

[0669] R^(1c1) is selected from the group consisting of:

[0670] —H, —F, —Cl, —Br, —CN, —CH₂NH₂, —CH₂OH, —CONH₂, —C(═NH)NH₂,—CO₂H, —CO₂Me, —SO₂Me, —SO₂NH₂, —OH, —NH₂, and —NO₂;

[0671] R^(1c2) is selected from the group consisting of:

[0672] —H, —F, —Cl, —Br, and —OCH₃;

[0673] R^(1c3) is selected from the group consisting of:

[0674] —H, —F, —Cl, —Br, —OCH₃, —NH₂, —CH₂NH₂, —CONH₂, —CONHMe, —CONMe₂;

[0675] G is selected from the group consisting of:

[0676] wherein:

[0677] R^(1b1) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0678] R^(1b2) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0679] R^(1b3) is selected from the group consisting of —Cl, —NH₂, —CH₃and —CF₃.

[0680] The following compounds are an embodiment of the presentinvention:

[0681] wherein:

[0682] R¹ is selected from the group consisting of:

[0683] —SO₂NH₂, —SO₂Me, —CH₂NH₂ and —CH₂NMe₂;

[0684] R^(1a) is selected from the group consisting of:

[0685] —H, —F, —Cl and —Br;

[0686] R^(1c) is selected from the group consisting of:

[0687] —H, —F, —Cl, —Br, —NH₂, —OH, —SO₂Me, —SO₂Et, —SO₂NH₂, —NO₂,—CH₂NH₂, —CN, —CONH₂, —CH₂OH;

[0688] G is selected from the group consisting of:

[0689] wherein:

[0690] R^(1b1) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0691] R^(1b2) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0692] R^(1b3) is selected from the group consisting of —Cl, —NH₂, —CH₃and —CF₃.

[0693] The following compounds are an embodiment of the presentinvention:

[0694] wherein:

[0695] R¹ is selected from the group consisting of:

[0696] —SO₂NH₂, —SO₂Me, —CH₂NH₂ and —CH₂NMe₂;

[0697] R^(1a) is selected from the group consisting of:

[0698] —H, —F, —Cl and —Br;

[0699] R^(1c1) is selected from the group consisting of:

[0700] —H, —F, —Cl, —Br, —NH₂, —OH, —SO₂Me, —SO₂Et, —SO₂NH₂, —NO₂,—CH₂NH₂, —CN, —CONH₂, —CH₂OH;

[0701] R^(1c2) is selected from the group consisting of:

[0702] —H, —F, —Cl and —Br;

[0703] G is selected from the group consisting of:

[0704] wherein:

[0705] R^(1b1) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0706] R^(1b2) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0707] R^(1b3) is selected from the group consisting of —Cl, —NH₂, —CH₃and —CF₃.

[0708] The following compounds are an embodiment of the presentinvention:

[0709] wherein:

[0710] A-Q is selected from the group consisting of:

[0711] wherein:

[0712] A is selected from the group consisting of:

[0713] R^(1a) is selected from the group consisting of —H, —F, —Cl and—Br;

[0714] R^(1c1) is selected from the group consisting of:

[0715] —H, —F, —Cl, —Br, —NH₂, —OH, —SO₂Me, —SO₂Et, —SO₂NH₂, —NO₂,—CH₂NH₂, —CN, —CONH₂, —CH₂OH;

[0716] R^(1c2) is selected from the group consisting of:

[0717] —H, —F, —Cl and —Br;

[0718] R^(1c3) is selected from the group consisting of:

[0719] —H, —F, —Cl and —Br;

[0720] G is selected from the group consisting of:

[0721] wherein:

[0722] R^(1b1) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0723] R^(1b2) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0724] R^(1b3) is selected from the group consisting of —Cl, —NH₂, —CH₃and —CF₃.

[0725] The following compounds are an embodiment of the presentinvention:

[0726] wherein:

[0727] A-Q is selected from the group consisting of:

[0728] wherein:

[0729] A is selected from the group consisting of:

[0730] R^(1a) is selected from the group consisting of:

[0731] —H, —F, —Cl and —Br;

[0732] R^(1b) is selected from the group consisting of:

[0733] —CH₃, —CF₃, —CH₂CH₃, —SO₂Me, —CONH₂ and —NHSO₂Me;

[0734] R^(1c1) is selected from the group consisting of:

[0735] —H, —F, —Cl, —Br, —NH₂, —OH, —SO₂Me, —SO2Et, —SO₂NH₂, —NO₂,—CH₂NH₂, —CN, —CONH₂, —CH₂OH;

[0736] R^(1c2) is selected from the group consisting of:

[0737] —H, —F, —Cl, —Br and —OMe;

[0738] R^(1c3) is selected from the group consisting of:

[0739] —H, —F, —Cl, —Br, —OH, —OCH₃, —NH₂, —CONH₂, —CH₂NH₂;

[0740] G is selected from the group consisting of:

[0741] wherein:

[0742] R^(1b1) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0743] R^(1b2) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0744] R^(1b3) is selected from the group consisting of —Cl, —NH₂, —CH₃and —CF₃.

[0745] The following compounds are an embodiment of the presentinvention:

[0746] wherein:

[0747] R¹ is selected from the group consisting of:

[0748] —SO₂NH₂, —SO₂CH₃ , —CN, —CONH₂, —CONH(CH₃), —CON(CH₃)₂, —CH₂NH₂,—CH₂NH(CH₃), —CH₂N(CH₃)₂;

[0749] R^(1a) is selected from the group consisting of:

[0750] —H, —F, —Cl and Br;

[0751] R^(1b) is selected from the group consisting of:

[0752] —CH₃ and —CF₃;

[0753] R^(1c1) is selected from the group consisting of:

[0754] —H, —F, —Cl, —Br, —CN, —CH₂NH₂, —CH₂OH, —CONH₂, —C(ONH)NH₂,—CO₂H, —CO₂Me, —SO₂Me, —SO₂NH₂, —OH, —NH₂, and —NO₂;

[0755] R^(1c2) is selected from the group consisting of:

[0756] —H, —F, —Cl and —Br;

[0757] R^(1c3) is selected from the group consisting of:

[0758] —H, —F, —Cl and —Br.

[0759] The following compounds are an embodiment of the presentinvention:

[0760] wherein:

[0761] R^(1a) is selected from the group consisting of:

[0762] —H, —F, —Cl and —Br;

[0763] R^(1b) is selected from the group consisting of:

[0764] —CH₃, —CF₃, —CH₂CH₃, —SO₂Me, —CONH₂ and —NHSO₂Me;

[0765] R^(1c1) is selected from the group consisting of:

[0766] —H, —F, —Cl, —Br, —NH₂, —OH, —SO₂Me, —SO₂Et, —SO₂NH₂, —NO₂,—CH₂NH₂, —CN, —CONH₂, —CH₂OH;

[0767] R^(1c2) is selected from the group consisting of:

[0768] —H, —F, —Cl, —Br and —OCH₃;

[0769] R^(1c3) is selected from the group consisting of:

[0770] —H, —F, —Cl, —Br, —OCH₃, —NH₂, —CH₂NH₂, —CONH₂, —CONHMe, —CONMe₂.

[0771] The following compounds are an embodiment of the presentinvention:

[0772] wherein:

[0773] A-Q is selected from the group consisting of:

[0774] wherein:

[0775] A is selected from the group consisting of:

[0776] R^(1a) is selected from the group consisting of:

[0777] —H, —F, —Cl and —Br;

[0778] R^(1c1) is selected from the group consisting of:

[0779] —H, —F, —Cl, —Br, —CN, —CH₂NH₂, —CH₂O H, —CONH₂, —C(═NH)NH₂,—CO₂H, —CO₂Me, —SO₂Me, —SO₂NH₂, —OH, —NH₂, and —NO₂;

[0780] R^(1c2) is sclected from the group consisting of:

[0781] —H, —F, —Cl, —Br, and —OCH₃;

[0782] R^(1c3) is selected from the group consisting of:

[0783] —H, —F, —Cl, —Br, —OCH₃, —NH₂, —CH₂NH₂, —CONH₂, —CONHMe, —CONMe₂;

[0784] G is selected from the group consisting of:

[0785] wherein:

[0786] R^(1b1) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0787] R^(1b2) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0788] R^(1b3) is selected from the group consisting of —Cl, —NH₂, —CH₃and —CF₃.

[0789] The following compounds are an embodiment of the presentinvention:

[0790] R¹ is selected from the group consisting of:

[0791] —SO₂NH₂, —SO₂CH₃, —CN, —CONH₂, —CONH(CH₃), —CON(CH₃)₂, —CH₂NH₂,—CH₂NH(CH₃), —CH₂N(CH₃)₂;

[0792] R^(1a) is selected from the group consisting of:

[0793] —H, —F, —Cl and —Br;

[0794] R^(1b) is selected from the group consisting of:

[0795] —H, —CH₃ and —CF₃;

[0796] R^(1c1) is selected from the group consisting of:

[0797] —H, —F, —Cl, —Br, —CN, —CH₂NH₂, —CH₂OH, —CONH₂, —C(═NH)NH₂,—CO₂H, —CO₂Me, —SO₂Me, —SO₂NH₂, —OH, —NH₂, and —NO₂;

[0798] R^(1c2) is selected from the group consisting of:

[0799] —H, —F, —Cl and —Br;

[0800] R^(1c3) is selected from the group consisting of:

[0801] —H, —F, —Cl and —Br.

[0802] The following compounds are an embodiment of the presentinvention:

[0803] wherein:

[0804] R¹ is selected from the group consisting of:

[0805] —SO₂NH₂, —SO₂CH₃, —CN, —CONH₂, —CONH(CH₃), —CON(CH₃)₂, —CH₂NH₂,—CH₂NH(CH₃), —CH₂N(CH₃)₂;

[0806] R^(1a) is selected from the group consisting of:

[0807] —H, —F, —Cl and —Br;

[0808] R^(1b) is selected from the group consisting of:

[0809] —H, —CH₃ and —CF₃;

[0810] R^(1c1) is selected from the group consisting of:

[0811] —H, —F, —CN, —CH₂NH₂, —CONH₂, —SO₂Me, —SO₂NH₂ and —NO₂;

[0812] R^(1c2) is selected from the group consisting of:

[0813] —H, —F, —Cl, —Br and —OCH₃;

[0814] R^(1c3) is selected from the group consisting of:

[0815] —H, —F, —Cl, —Br, —OCH₃, —NH₂, —CH₂NH₂, —CONH₂, —CONHMe, —CONMe₂.

[0816] The following compounds are an embodiment of the presentinvention:

[0817] wherein:

[0818] A-Q is selected from the group consisting of:

[0819] wherein:

[0820] A is selected from the group consisting of:

[0821] R^(1a) is selected from the group consisting of:

[0822] —H, —F, —Cl and —Br;

[0823] R^(1b) selected from the group consisting of:

[0824] —H, —CH₃ and —CF₃;

[0825] R^(1c1) is selected from the group consisting of:

[0826] —H, —F, —Cl, —Br, —CN, —CH₂NH₂, —CH₂OH, —CONH₂, —C(═NH)NH₂,—CO₂H, —CO₂Me, —SO₂Me, —SO₂NH₂, —OH, —NH₂, and —NO₂;

[0827] R^(1c2) is selected from the group consisting of:

[0828] —H, —F, —Cl and —Br;

[0829] R^(1c3) is selected from the group consisting of:

[0830] —H, —F, —Cl and —Br.

[0831] The following compounds are an embodiment of the presentinvention:

[0832] wherein:

[0833] A-Q is selected from the group consisting of:

[0834] wherein:

[0835] A is selected from the group consisting of:

[0836] R^(1a) is selected from the group consisting of:

[0837] —H, —F, —Cl and —Br;

[0838] R^(1b) is selected from the group consisting of:

[0839] —H, —CH₃ and —CF₃;

[0840] R^(1c1) is selected from the group consisting of:

[0841] —H, —F, —CN, —CH₂NH₂, —CONH₂, —SO₂Me, —SO₂NH₂ and —NO₂;

[0842] R^(1c2) is selected from the group consisting of:

[0843] —H, —F, —Cl, —Br and —OCH₃;

[0844] R^(1c3) is selected from the group consisting of:

[0845] —H, —F, —Cl, —Br, —OCH₃, —NH₂, —CH₂NH₂, —CONH₂, —CONHMe, —CONMe₂.

[0846] The following compounds are an embodiment of the presentinvention:

[0847] Wherein:

[0848] R¹ is selected from the group consisting of:

[0849] —SO₂NH₂, —SO₂Me, —CH₂NH₂ and —CH₂NME₂;

[0850] R^(1a) is selected from the group consisting of:

[0851] —H, —F, —Cl and —Br;

[0852] R^(1c1) is selected from the group consisting of:

[0853] —H, —F, —Cl, —Br, —NH₂, —OH, —SO₂Me, —SO₂Et, —SO₂NH₂, —NO₂,—CH₂NH₂, —CN, —CONH₂, —CH₂OH;

[0854] R^(1c2) and R^(1c3) are independently selected from the groupconsisting of:

[0855] —H, —F, —Cl and —Br;

[0856] G is selected from the group consisting of:

[0857] wherein:

[0858] R^(1b1) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0859] R^(1b2) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0860] R^(1b3) is selected from the group consisting of —Cl, —NH₂, —CH₃and —CF₃.

[0861] The following compounds are an embodiment of the presentinvention:

[0862] wherein:

[0863] R¹ is selected from the group consisting of:

[0864] —SO₂NH₂, —SO₂Me, —CH₂NH₂ and —CH₂NMe₂;

[0865] R^(1a) is selected from the group consisting of:

[0866] —H, —F, —Cl and —Br;

[0867] R^(1c1) is selected from the group consisting of:

[0868] —H, —F, —Cl, —Br, —NH₂, —OH, —SO₂Me, —SO₂Et, —SO₂NH₂, —NO₂,—CH₂NH₂, —CN, —CONH₂, —CH₂OH;

[0869] R^(1c2) and R^(1c3) are independently selected from the groupconsisting of:

[0870] —H, —F, —Cl and —Br;

[0871] G is selected from the group consisting of:

[0872] wherein:

[0873] R^(1b1) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0874] R^(1b2) is selected from the group consisting of —H, —CH₃ and—CF₃;

[0875] R^(1b3) is selected from the group consisting of —Cl, —NH₂, —CH₃and —CF₃.

[0876] This invention also encompasses all pharmaceutically acceptableisomers, salts, hydrates and solvates of the compounds of the formula(I). In addition, the compounds of formula (I) can exist in variousisomeric and tautomeric forms, and all such forms are meant to beincluded in the invention, along with pharmaceutically acceptable salts,hydrates and solvates of such isomers and tautomers.

[0877] The compounds of this invention may be isolated as the free acidor base or converted to salts of various inorganic and organic acids andbases. Such salts are within the scope of this invention. Non-toxic andphysiologically compatible salts are particularly useful although otherless desirable salts may have use in the processes of isolation andpurification.

[0878] A number of methods are useful for the preparation of the saltsdescribed above and are known to those skilled in the art. For example,the free acid or free base form of a compound of one of the formulasabove can be reacted with one or more molar equivalents of the desiredacid or base in a solvent or solvent mixture in which the salt isinsoluble, or in a solvent like water after which the solvent is removedby evaporation, distillation or freeze drying. Alternatively, the freeacid or base form of the product may be passed over an ion exchangeresin to form the desired salt or one salt form of the product may beconverted to another using the same general process.

[0879] Preparation of Compounds

[0880] The compounds of the present invention may be synthesized bystandard organic chemical synthetic methods as described and referencedin standard textbooks. These methods are well known in the art. See,e.g., March, “Advanced Organic Chemistry”, John Wiley & Sons, New York,,1992; Joule, Mills and Smith, “Heterocyclic Chemistry”, Chapman & Hall,London, 1995, et seq.

[0881] Starting materials used in any of these methods are commerciallyavailable from chemical vendors such as Aldrich, Fluka, Lancaster, TCI,Maybridge, Frontier, Fluorochem, Alfa Aesar, and the like, or may bereadily synthesized by known procedures.

[0882] Reactions are carried out in standard laboratory glassware andreaction vessels under reaction conditions of standard temperature andpressure, except where otherwise indicated.

[0883] During the syntheses of these compounds, the functional groups ofthe substitutents are optionally protected by blocking groups to preventcross reaction. Examples of suitable protective groups and their use aredescribed in Kocienski, “Protecting Groups”, Thieme, Stuttgart, 1994;Greene and Wuts, “Protective Groups in Organic Synthesis”, John Wiley &Sons, New York, 1999, and the disclosures of which are incorporatedherein by reference.

[0884] Non-limiting exemplary synthesis schemes are outlined directlybelow, and specific steps are described in the Examples. The reactionproducts are isolated and purified by conventional methods, typically bysolvent extraction into a compatible solvent. The products may befurther purified by flash column chromatography, reverse-phasepreparative high performance liquid chromatography (HPLC) with highpurity water and acetonitrile, or other appropriate methods.

[0885] General Synthesis

[0886] General synthesis for compounds with a N-linked G ring isoutlined in Scheme 1. A′, Q′, D′, E′, J′ and X′ are protected functionalstructures which can be converted to A, Q, D, E, J and X respectively.For formation of the N-linked G ring, the appropriate aromatic amineprecursor is treated under conditions described in Joule, Mills andSmith, “Heterocyclic Chemistry”, Chapman & Hall, London, 1995, or thereferences cited therein, or as described later in the preparationsection to give the G ring.

[0887] Scheme 2 shows the general synthesis of compounds with a N-linkedpyrazole G ring. Appropriately protected aromatic amines are convertedto aromatic hydrazines by reduction of their diazonium salts. Thehydrazines are condensed with 1,3-diketones to yield the pyrazolestructures.

[0888] Scheme 3 shows the general synthesis of compounds with a N-linkedtriazole G ring. An appropriately protected aromatic amine is convertedto aromatic azide from its diazonium salt. The azide is condensed withan alkyne to yield the triazole structure.

[0889] Scheme 4 shows the general synthesis of compounds with a N-linkedtetrazole G ring. An appropriately protected aromatic amine is acylatedwith ethyl chlorooxoacetate. The resulting amide can be converted to thetetrazole by a literature method (Journal of Organic Chemistry, 56, 2395(1991)). Other methods (Synthesis, 767 (1993); Journal of OrganicChemistry, 58, 32 (1993); Bioorganic & Medicinal Chemistry Letters, 6,1015 (1996)) can also be used.

[0890] General synthesis for compounds with a C-linked G ring isoutlined in Scheme 5. A′, Q′, D′, E′, J′ and X′ are protected functionalstructures which can be converted to A, Q, D, E, J and X respectively.For formation of the C-linked G ring, the appropriate aromatic aldehydeprecursor is treated under conditions described in Joule, Mills andSmith, “Heterocyclic Chemistry”, Chapman & Hall, London, 1995, or thereferences cited therein, or as described later in the preparationsection to give the G ring. The C-linked G ring can also be connected toaromatic X or aromatic D using Suzuki cross-coupling method (ChemicalReviews, 95, 2457 (1995)).

[0891] Scheme 6 shows the general synthesis of compounds with a C-linkedisoxazole G ring. A substituted aromatic aldehyde is reacted withhydroxylamine and then chlorinated to yield the hydroximinoyl choride(Journal of Organic Chemistry, 45, 3916 (1980)). It is treated withtriethylamine to generate nitrile oxide in situ, which is reacted withmethyl trans-3-mthoxyacrylate or methyl propiolate to give the isoxazolestructure (Chemical Letters, 1, 85 (1987)).

[0892] Scheme 7 shows the general synthesis of compounds with a C-linkedthiozole G ring. A substituted aromatic aldehyde is reacted with ethyldiazoacetate in presence of tin(II) chloride to afford thebeta-ketoester. It is then converted to thiazole.

[0893] Compositions and Formulations

[0894] The compounds of this invention may be isolated as the free acidor base or converted to salts of various inorganic and organic acids andbases. Such salts are within the scope of this invention. Non-toxic andphysiologically compatible salts are particularly useful although otherless desirable salts may have use in the processes of isolation andpurification.

[0895] A number of methods are useful for the preparation of the saltsdescribed above and are known to those skilled in the art. For example,reaction of the free acid or free base form of a compound of thestructures recited above with one or more molar equivalents of thedesired acid or base in a solvent or solvent mixture in which the saltis insoluble, or in a solvent like water after which the solvent isremoved by evaporation, distillation or freeze drying. Alternatively,the free acid or base form of the product may be passed over an ionexchange resin to form the desired salt or one salt form of the productmay be converted to another using the same general process.

[0896] Diagnostic applications of the compounds of this invention willtypically utilize formulations such as solution or suspension. In themanagement of thrombotic disorders the compounds of this invention maybe utilized in compositions such as tablets, capsules or elixirs fororal administration, suppositories, sterile solutions or suspensions orinjectable administration, and the like, or incorporated into shapedarticles. Subjects in need of treatment (typically mammalian) using thecompounds of this invention can be administered dosages that willprovide optimal efficacy. The dose and method of administration willvary from subject to subject and be dependent upon such factors as thetype of mammal being treated, its sex, weight, diet, concurrentmedication, overall clinical condition, the particular compoundsemployed, the specific use for which these compounds are employed, andother factors which those skilled in the medical arts will recognize.

[0897] Formulations of the compounds of this invention are prepared forstorage or administration by mixing the compound having a desired degreeof purity with physiologically acceptable carriers, excipients,stabilizers etc., and may be provided in sustained release or timedrelease formulations. Acceptable carriers or diluents for therapeuticuse are well known in the pharmaceutical field, and are described, forexample, in Remington's Pharmaceutical Sciences, Mack Publishing Co.,(A. R. Gennaro edit. 1985). Such materials are nontoxic to therecipients at the dosages and concentrations employed, and includebuffers such as phosphate, citrate, acetate and other organic acidsalts, antioxidants such as ascorbic acid, low molecular weight (lessthan about ten residues) peptides such as polyarginine, proteins, suchas serum albumin, gelatin, or immunoglobulins, hydrophilic polymers suchas polyvinalpyrrolidinone, amino acids such as glycine, glutamic acid,aspartic acid, or arginine, monosaccharides, disaccharides, and othercarbohydrates including cellulose or its derivatives, glucose, mannoseor dextrins, chelating agents such as EDTA, sugar alcohols such asmannitol or sorbitol, counterions such as sodium and/or nonionicsurfactants such as Tween, Pluronics or polyethyleneglycol.

[0898] Dosage formulations of the compounds of this invention to be usedfor therapeutic administration must be sterile. Sterility is readilyaccomplished by filtration through sterile membranes such as 0.2 micronmembranes, or by other conventional methods. Formulations typically willbe stored in lyophilized form or as an aqueous solution. The pH of thepreparations of this invention typically will be between about 3 andabout 11, more preferably from about 5 to about 9 and most preferablyfrom about 7 to about 8. It will be understood that use of certain ofthe foregoing excipients, carriers, or stabilizers will result in theformation of cyclic polypeptide salts. While the preferred route ofadministration is by injection, other methods of administration are alsoanticipated such as intravenously (bolus and/or infusion),subcutaneously, intramuscularly, colonically, rectally, nasally orintraperitoneally, employing a variety of dosage forms such assuppositories, implanted pellets or small cylinders, aerosols, oraldosage formulations and topical formulations such as ointments, dropsand dermal patches. The compounds of this invention are desirablyincorporated into shaped articles such as implants which may employinert materials such as biodegradable polymers or synthetic silicones,for example, Silastic, silicone rubber or other polymers commerciallyavailable.

[0899] The compounds of this invention may also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles and multilamellar vesicles. Liposomes can beformed from a variety of lipids, such as cholesterol, stearylamine orphosphatidylcholines.

[0900] The compounds of this invention may also be delivered by the useof antibodies, antibody fragments, growth factors, hormones, or othertargeting moieties, to which the compound molecules are coupled. Thecompounds of this invention may also be coupled with suitable polymersas targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxy-propyl-methacrylamide-phenol,polyhydroxyethyl-aspartamide-phenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the factor Xainhibitors of this invention may be coupled to a class of biodegradablepolymers useful in achieving controlled release of a drug, for examplepolylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross linked or amphipathic block copolymers of hydrogels. Polymers andsemipermeable polymer matrices may be formed into shaped articles, suchas valves, stents, tubing, prostheses and the like.

[0901] Therapeutic compound liquid formulations generally are placedinto a container having a sterile access port, for example, anintravenous solution bag or vial having a stopper pierceable byhypodermic injection needle.

[0902] Therapeutically effective dosages may be determined by either invitro or in vivo methods. For each particular compound of the presentinvention, individual determinations may be made to determine theoptimal dosage required. The range of therapeutically effective dosageswill naturally be influenced by the route of administration, thetherapeutic objectives, and the condition of the patient. For injectionby hypodermic needle, it may be assumed the dosage is delivered into thebody's fluids. For other routes of administration, the absorptionefficiency must be individually determined for each inhibitor by methodswell known in pharmacology. Accordingly, it may be necessary for thetherapist to titer the dosage and modify the route of administration asrequired to obtain the optimal therapeutic effect. The determination ofeffective dosage levels, that is, the dosage levels necessary to achievethe desired result, will be within the ambit of one skilled in the art.Typically, applications of compound are commenced at lower dosagelevels, with dosage levels being increased until the desired effect isachieved.

[0903] A typical dosage might range from about 0.001 mg/kg to about 1000mg/kg, preferably from about 0.01 mg/kg to about 100 mg/kg, and morepreferably from about 0.10 mg/kg to about 20 mg/kg. Advantageously, thecompounds of this invention may be administered several times daily, andother dosage regimens may also be useful.

[0904] Typically, about 0.5 to about 500 mg of a compound or mixture ofcompounds of this invention, as the free acid or base form or as apharmaceutically acceptable salt, is compounded with a physiologicallyacceptable vehicle, carrier, excipient, binder, preservative,stabilizer, dye, flavor etc., as called for by accepted pharmaceuticalpractice. The amount of active ingredient in these compositions is suchthat a suitable dosage in the range indicated is obtained.

[0905] Typical adjuvants which may be incorporated into tablets,capsules and the like are a binder such as acacia, corn starch orgelatin, and excipient such as microcrystalline cellulose, adisintegrating agent like corn starch or alginic acid, a lubricant suchas magnesium stearate, a sweetening agent such as sucrose or lactose, ora flavoring agent. When a dosage form is a capsule, in addition to theabove materials it may also contain a liquid carrier such as water,saline, a fatty oil. Other materials of various types may be used ascoatings or as modifiers of the physical form of the dosage unit.Sterile compositions for injection can be formulated according toconventional pharmaceutical practice. For example, dissolution orsuspension of the active compound in a vehicle such as an oil or asynthetic fatty vehicle like ethyl oleate, or into a liposome may bedesired. Buffers, preservatives, antioxidants and the like can beincorporated according to accepted pharmaceutical practice.

[0906] In practicing the methods of this invention, the compounds ofthis invention may be used alone or in combination, or in combinationwith other therapeutic or diagnostic agents. In certain preferredembodiments, the compounds of this inventions may be coadministeredalong with other compounds typically prescribed for these conditionsaccording to generally accepted medical practice, such as anticoagulantagents, thrombolytic agents, or other antithrombotics, includingplatelet aggregation inhibitors, tissue plasminogen activators,urokinase, prourokinase, streptokinase, heparin, aspirin, or warfarin.The compounds of this invention can be utilized in vivo, ordinarily inmammals such as primates, such as humans, sheep, horses, cattle, pigs,dogs, cats, rats and mice, or in vitro.

[0907] The preferred compounds of the present invention arecharacterized by their ability to inhibit thrombus formation withacceptable effects on classical measures of coagulation parameters,platelets and platelet function, and acceptable levels of bleedingcomplications associated with their use. Conditions characterized byundesired thrombosis would include those involving the arterial andvenous vasculature.

[0908] With respect to the coronary arterial vasculature, abnormalthrombus formation characterizes the rupture of an establishedatherosclerotic plaque which is the major cause of acute myocardialinfarction and unstable angina, as well as also characterizing theocclusive coronary thrombus formation resulting from either thrombolytictherapy or percutaneous transluminal coronary angioplasty (PTCA).

[0909] With respect to the venous vasculature, abnormal thrombusformation characterizes the condition observed in patients undergoingmajor surgery in the lower extremities or the abdominal area who oftensuffer from thrombus formation in the venous vasculature resulting inreduced blood flow to the affected extremity and a predisposition topulmonary embolism. Abnormal thrombus formation further characterizesdisseminated intravascular coagulopathy commonly occurs within bothvascular systems during septic shock, certain viral infections andcancer, a condition wherein there is rapid consumption of coagulationfactors and systemic coagulation which results in the formation oflife-threatening thrombi occurring throughout the microvasculatureleading to widespread organ failure.

[0910] The compounds of this present invention, selected and used asdisclosed herein, are believed to be useful for preventing or treating acondition characterized by undesired thrombosis, such as (a) thetreatment or prevention of any thrombotically mediated acute coronarysyndrome including myocardial infarction, unstable angina, refractoryangina, occlusive coronary thrombus occurring post-thrombolytic therapyor post-coronary angioplasty, (b) the treatment or prevention of anythrombotically mediated cerebrovascular syndrome including embolicstroke, thrombotic stroke or transient ischemic attacks, (c) thetreatment or prevention of any thrombotic syndrome occurring in thevenous system including deep venous thrombosis or pulmonary embolusoccurring either spontaneously or in the setting of malignancy, surgeryor trauma, (d) the treatment or prevention of any coagulopathy includingdisseminated intravascular coagulation (including the setting of septicshock or other infection, surgery, pregnancy, trauma or malignancy andwhether associated with multi-organ failure or not), thromboticthrombocytopenic purpura, thromboanguitis obliterans, or thromboticdisease associated with heparin induced thrombocytopenia, (e) thetreatment or prevention of thrombotic complications associated withextracorporeal circulation (e.g. renal dialysis, cardiopulmonary bypassor other oxygenation procedure, plasmapheresis), (f) the treatment orprevention of thrombotic complications associated with instrumentation(e.g. cardiac or other intravascular catheterization, intra-aorticballoon pump, coronary stent or cardiac valve), and (g) those involvedwith the fitting of prosthetic devices.

[0911] Anticoagulant therapy is also useful to prevent coagulation ofstored whole blood and to prevent coagulation in other biologicalsamples for testing or storage. Thus the compounds of this invention canbe added to or contacted with any medium containing or suspected tocontain factor Xa and in which it is desired that blood coagulation beinhibited, e.g., when contacting the mammal's blood with material suchas vascular grafts, stents, orthopedic prostheses, cardiac stents,valves and prostheses, extra corporeal circulation systems and the like.

[0912] Without further description, it is believed that one of ordinaryskill in the art can, using the preceding description and the followingillustrative examples, make and utilize the compounds of the presentinvention and practice the claimed methods. The following workingexamples therefore, specifically point out preferred embodiments of thepresent invention, and are not to be construed as limiting in any waythe remainder of the disclosure.

EXAMPLES Example 1

[0913]

[0914] Step 1. To the solution of 2-naphthylboronic acid (5.00 g, 29.1mmol) and ethyl 3-methylpyrazole-5-carboxylate (4.48 g, 29.1 mmol) in100 mL dry dichloromethane (DCM) were added pyridine (4.7 mL, 58.2 mmol)and anhydrous powder of copper(II) acetate (7.94 g, 43.7 mmol). Someactivated molecular sieve powder was added afterwards. The resultingslurry was stirred for 2 days under argon. The mixture was diluted withDCM. It was filtered through a celite bed. The blue filtrate was washedwith water (X2), dried over MgSO₄, concentrated, purified by silicacolumn to yield ethyl 3-methyl-1-(2-naphthyl)-1H-pyrazole-5-carboxylateand its regioisomer in a 1:1 ratio in 70% yield. Rf 0.59 (1:2 EtOAc:hexane), M+H 281; regioisomer, ethyl5-methyl-1-(2-naphthyl)-1H-pyrazole-3-carboxylate, Rf 0.44 (1:2EtOAc:hexane). ES-MS: (M+H)⁺281.

[0915] Step 2. To a solution of2′N-tert-butylaminosulfonyl-[1,1′]-biphenyl-4-ylamine (50 mg, 0.16 mmol)in 1 iL DCM was added trimethylaluminum (2.OM in hexane, 0.41 mL, 0.82mmol) under argon at room temperature. After being stirred for 30minutes, to the mixture was added the above-prepared ester (46 mg, 0.16mmol) in 1 mL DCM. The resulting mixture was stirred overnight. Thereaction was quenched using 5 mL saturated Rochelle salt aq solution.The mixture was extracted using DCM (×3). The organic phases werecombined, dried, rotovaped and subjected on flash column to give thecoupled product in 52% yield (46 mg). Rf 0.46 (1:1 EtOAc: hexane).ES-MS: (M+H)⁺539.

[0916] Step 3. The above-prepared compound (42 mg, 0.078 mmol) wasplaced in 3 mL trifluoroacetic acid (TFA). The solution was stirred in60° C. bath for 30 minutes. TFA was removed on rotovap. The residue wasdissolved in methanol and purified by preparative HPLC to afford thetitle compound in 95% yield. ES-MS: (M+H)⁺483.

Example 2

[0917]

[0918] Step 1. A mixture of tin(II) chloride (2.08 g, 10.96 mmol) andethyl diazoacetate (2.76 mL, 26.28 mmol) in 50 mL DCM was stirred for 2hours. Naphthalene-2-carbaldehyde was added. After stirred at roomtemperature for 18 hours, the mixture was concentrated, dissolved inEtOAc, washed with water (×3), dried and evaporated. The crude materialwas purified to give product ethyl 3-(2-naphthyl)-3-oxoprppionate.Rf0.61 (1:1 EtOAc:hexane). ES-MS: (M+H)⁺243.

[0919] Step 2. To a solution of the above-prepared ester (240 mg, 1mmol) in 15 mL MeCN at 65° C. was added hydroxy(tosyloxy)iodobenzene(430 mg, 1.1 mmol). After stirred for 1 hour, to the mixture was addedthiourea (83 mg, 1.1 mmol). The resulting mixture was stirred overnightat 65° C. The solution was cooled and concentrated. The residue wasdissolved in EtOAc, washed with brine, dried over MgSO₄, and evaporatedto give crude 2-methyl-4-(2-naphthyl)-5-(carboethoxy)thiazole. Rf 0.64(1:3 EtOAc:hexane). ES-MS: (M+H)⁺298.

[0920] Step 3. To a solution of the above-prepared product (148 mg, 0.50mmol) and 2′N-tert-butylaminosulfonyl-[1,1′]-biphenyl-4-ylamine (152 mg,0.50 mmol) in 3 mL DCM was added trimethylaluminum (2.0M in hexane, 0.75mL, 1.5 mmol), and the mixture was stirred at room temperature for 20hours. The reaction was neutralized with 4 mL 1N HCl and extracted withEtOAc. The organic layer was washed with brine, dried over MgSO₄, andconcentrated to give the coupling product (170 mg, 61%). Rf0.25 (1:3EtOAc:hexane). ES-MS: (M+H)⁺556.

[0921] Step 4. The above-prepared product (100 mg) was placed in 3 mLTFA. The solution was stirred in 80° C. bath for 60 minutes. TFA wasremoved on rotovap. The residue was dissolved in methanol and purifiedby preparative HPLC to afford the title compound in over 90% yield.ES-MS: (M+H)⁺500.

Example 3

[0922]

[0923] Step 1. 3-Amino-2-naphthoic acid (40.4 g, 216 mmol) was placed in200 mL concentrated HCl. At 0° C., the slurry was stirred vigorouslyusing a mechanical stirring blade. To it was added a cold solution ofsodium nitrite (29.8 g, 432 mmol) in 70 mL water. After completion, thecold slurry was stirred for 30 minutes at 0° C. To it was added coldtetrafluoroboric acid (48 wt. % in water, 56 mL, 432 mmol). Afterstirred at 0° C. for 30 minutes, the solid was filtered using a Buchnerfunnel. The soild cake was carefuilly rinsed with cold water (10 mL ×2),cold tetrafluoroboric acid (10 mL ×2) and cold ethanol (5 mL ×2). Thesolid was dried in vacuuo. It was then placed in 300 mL xylene andrefluxed overnight. Xylenie was removed on rotovap. The residue wasacidified to pH 1 with aq HCl and taken into EtOAc. It was washed withbrine (×2), dried, evaporated to give 3-fluoro-2-naphthoic acid (32.6 g,78%). ES-MS: (M+H)⁺191.

[0924] Step 2. The above-prepared acid (14.7 g, 77 mmol) was dissolvedin 200 mL CHCl₃. To it was added 0.5 mL dry DMF. Then at roomtemperature, oxalyl chloride (20 mL, 232 mmol) was added dropwise. Thereaction solution was stirred for overnight. All solvent was removed invacuuo. The residue was pumped till dryness. It was dissolved in 150 mLdry dioxane, chilled to 0° C. and vigorously stirred. To it, at the coldtempareture, was added the cold solution of sodium azide (10 g, 155mmol, in 30 mL water and 15 mL dioxane) in small portions. The reactionwas allowed for 2 hours at 0° C. The solvent was removed in vacuuo. Theresidue was taken into EtOAc and washed with brine (×3). The organicphase was dried and evaporated to dryness in vacuuo to give3-fluoro-2-naphthoyl azide. Rf 0.83 (1:1 EtOAc:hexane). It was dissolvedin 80 mL DMF. To it was added 40 mL water. The milky mixture wasrefluxed overnight. The solvent was removed in vacuuo. The residue wastaken into EtOAc, and washed with brine (×2). The organic phase wasdried, concentrated and purified with flash silica column to yield3-fluoro-2-naphthylamine (8.1 g, 65%). Rf 0.40 (1:3 EtOAc:hexane).ES-MS: (M+H)⁺162.

[0925] Step 3. The above-prepared compound (7.5 g, 46 mmol) was placedin 50 mL concentrate HCl. The mixture was vigorously stirred in icebath. To it was dropwise added cold sodium nitrite (3.8 g, 55 mmol)solution in 10 mL water. After completion, the mixture was stirred at 0°C. for half an hour. At 0° C., to it was dropwise added cold SnCl₂.2H₂O(26.3 g, 116 mmol) solution in 20 mL concentrate HCl. The slurry wasstiffed for half an hour at 0° C., chilled, and filtered through aBuchner funnel to isolate the solid hydrazine. It was dried in vacuuo.The solid hydrazine was dissolved in 100 mL glacial acetic acid. To itwere added ethyl 2-N-(methoxy)imino-4-oxopentanoate (10.4 g, 56 mmol,prepared from ethyl 2,4-dioxovalerate and methoxylamine hydrogenchloride in ethanol) and 50 mL THF. The mixture was refluxed for 2hours. The solvent was removed in vacuuo. The residue was taken intoEtOAc, washed with brine and water. The organic phase was dried,concentrated and purified with flash column to yield ethyl3-methyl-1-(3-fluoro-2-naphthyl)-1H-pyrazole-5-carboxytate (9.0 g, 65%).Rf 0.52 (1:2 EtOAc:hexane). ES-MS: (M+H)⁺299.

[0926] Step 4. To a solution of2′-N-tert-butylaniinosulfonyl-[1,1′]-biphenyl-4-ylamine (77mg, 0.25mmol) in 1mL dry DCM was added trimethylaluminum (2.0M in hexane, 0.51mL, 1.0 mmol). The mixture was stirred for 20 minutes. Theabove-prepared ester (50 mg, 0.17 mmol) was dissolved in 3 mL dry DCMand added into the aluminum mixture. The reaction was stirred at roomtemperature for overnight and quenched using saturated Rochelle's saltaq solution. It was extracted with CHCl₃ (×3). The organic phases werecombined, dried, concentrated and purified with flash column to yieldthe coupling product (85 mg, 90%). Rf 0.45 (1:1 EtOAc:hexane). ES-MS:(M+H)⁺557.

[0927] Step 5. The above-prepared product was placed into 3 mL TFA. Themixture was stirred overnight at room temperature. It was evaporated,dissolved in methanol, purified with prep UPLC to afford the titlecompound in over 90% yield.). ES-MS: (M+H)⁺501.

Example 4

[0928]

[0929] Step 1. The preparation of ethyl3-methyl-1-(3-fluoro-2-naphthyl)-1H-pyrazole-5-carboxylate was the sameas that in Step 3 for Example 3. This ester (13.2 g, 44 mmol) wasdissolved in 80 mL methanol. To it were added LiOH.H₂O (3.7 g, 49 mmol)and 40 mL water. The mixture was stirred for overnight at roomtemperature. It was evaporated in vacuuo to remove methanol. The residuewas acidified with 1N HCI till pH 1. The mixture was extracted withEtOAc (×4). The organic extracts were combined, dried, evaporated andpumped to dryness to afford3-methyl-1-(3-fluoro-2-naphthyl)-1H-pyrazolecarboxylic acid in over 90%yield. ES-MS: (M+H)⁺271.

[0930] Step 2. The above-prepared acid (33 mg, 0.12 mmol),2′-N-tert-butylaminosulfonyl-3-fluoro-[1,1′]-biphenyl-4-ylamine (77 mg,0.24 mmol) and catalytic amount of DMAP (5 mg) were dissolved in 2 mLpyridine. The solution was stirred at 0° C. To it was added POCl₃ (45μL,0.48 mmol). The mixture was stirred for 1 hour and quenched with icechips. To it was added EtOAc. It was washed with brine (×2), dried, andconcentrated. To the residue was added 3 mL TFA. The mixture was stirredat 60° C. for 1 hour, concentrated, dissolved in methanol and subjectedon prep HPLC to afford the title compound in 50% yield (31 mg). ES-MS:(M+H)⁺519.

Example 5

[0931]

[0932] This compound was prepared by the same methodology described forExample 4 with2′-N-tert-butylaminosulfonyl-3-chloro-[1,1′]-biphenyl-4-ylaminesubstituted for2′-N-tert-butylaminosulfonyl-3-fluoro-[1,1′]-biphenyl-4-yl amine. ES-MS:(M+H)⁺535.

Example 6

[0933]

[0934] This compound was prepared by the same methodology described forExample 4 with2′-N-tert-butylaminosulfonyl-3-bromo-[1,1′]-biphenyl-4-ylaminesubstituted for2′-N-tert-butylaminosulfonyl-3-fluoro-[1,1′]-biphenyl-4-ylamine. ES-MS:(M+H)⁺579, 581 (Br pattern).

Example 7

[0935]

[0936] This compound was prepared by the same methodology described forExample 4 with 2-amino-5-(2-(N-tert-butylaminosulfonyl)phenyl)pyridinesubstituted for2′-N-tert-butylaminosulfonyl-3-fluoro-[1,1′]-biphenyl-4-ylamine. ES-MS:(M+H)⁺502.

Example 8

[0937]

[0938] This compound was prepared by the same methodology described forExample 4 with 2-amino-5-(2-(N-tert-butylaminosulfonyl)phenyl)pyrimidinesubstituted for2′-N-tert-butylarninosulfonyl-3-fluoro-[1,1′]-biphenyl-4-ylamine. ES-MS:(M+H)⁺503.

Example 9

[0939]

[0940] This compound was prepared by the same methodology described forExample 4 with 2′-cyano-[1,1′]-biphenyl-4-ylamine substituted2′-N-tert-butylaminosulfonyl-3-fluoro-[1,1′]-biphenyl-4-ylamine, withoutthe TFA treatment. ES-MS: (M+H)⁺447.

Example 10

[0941]

[0942] The title compound (40 mg, 0.09 mmol) of Example 9 was dissolvedin 2 mL dry DMF. At 0° C., to it were added sodium borohydride (27 mg,0.72 mmol) and anhydrous Co(II) chloride (23 mg, 0.18 mmol). The mixturewas stirred for 2 hours and quenched with 1 mL acetic acid. The mixturewas evaporated, dissolved in methanol, filtered, loaded on prep HPLC toafford the title compound in 60% yield. ES-MS: (M+H)⁺451.

Example 11

[0943]

[0944] The title compound (40 mg, 0.09 mmol) of Example 9 was dissolvedin 2 mL dry DMF. At 0° C., to it were added sodium borohydride (27 mg,0.72 mmol) and anhydrous Co(II) chloride (23 mg, 0.18 mmol). The mixturewas stirred for 2 hours. To it was added 10 mL acetone. The mixture wasstirred for 1 hour at room temperature. The reaction was quenched with 1mL acetic acid. The mixture was evaporated, dissolved in methanol,filtered, loaded on prep HPLC to afford the title compound in 50% yield.ES-MS: (M+H)⁺493.

Example 12

[0945]

[0946] This compound was prepared by the same methodology described forExample 4 with 2′-(N-dimethylamino)methyl- [1,1′]-biphenyl-4-ylaminesubstituted for2′-N-tert-butylaminosulfonyl-3-fluoro-[1,1′]-biphenyl-4-ylamine, withoutthe TFA treatment. ES-MS: (M+H)⁺479.

Example 13

[0947]

[0948] Step 1. The preparation of3-methyl-1-(3-fluoro-2-naphthyl)-1H-pyrazolecarboxylic acid was the sameas that in Step 1 of Example 4.

[0949] Step 2. This acid (65 mg, 0.24 mmol), 4-aminobenzonitrile (57 mg,0.48 mmol) and DMAP (5 mg) were dissolved in 3 mL pyridine. The solutionwas stirred at 0° C. To it was added POCl₃ (90 μL, 0.96 mmol). Themixture was stirred for 1 hour. The reaction was then quenched with icechips. It was diluted with EtOAc. The organic phase was washed withbrine (×2). It was dried, concentrated and purified with flash column toafford the coupling product (60 mg, 68%). Rf 0.40 (1:1 EtOAc:hexane).ES-MS: (M+H)⁺371.

[0950] Step 3. The above-prepared nitrile was dissolved in 10 mL drymethanol. It was chilled and stirred in an ice bath. To this solutionwas bubbled dry HCl gas via a long needle till saturation reached(indicated by a blown-up balloon attached on the top of the reactionflask). The resulting solution was stirred overnight. ES-MS: (M+H)⁺403.The solvent was removed in vacuuo. The residue was pumped to dryness.The solid was dissolved in 5 mL dry methanol. To it was added anhydrousN-methylethylenediamine (0.5 mL). The mixture was refluxed for 1 hour,concentrated and loaded on prep HPLC to afford the title compound in 80%yield. ES-MS: (M+H)⁺428.

Example 14

[0951]

[0952] This compound was prepared by the same methodology described forExample 13 with pyrrolidine substituted for N-methylethylenediamine.ES-MS: (M+H)⁺442.

Example 15

[0953]

[0954] This compound was prepared by the same methodology described forExample 13 with piperidine substituted for N-methylethylenediamine.ES-MS: (M+H)⁺456.

Example 16

[0955]

[0956] This compound was prepared by the same methodology described forExample 13 with dimethylamine (commercial 2M solution in THF)substituted for N-methylethylenediamine. ES-MS: (M+H)⁺416.

Example 17

[0957]

[0958] This compound was prepared by the same methodology described forExample 13 with thiomorpholine substituted for N-methylethylenediamine.ES-MS: (M+H)⁺474.

Example 18

[0959]

[0960] This compound was prepared by the same methodology described forExample 13 with morpholine substituted for N-methylethylenediamine.ES-MS: (M+H)⁺458.

Example 19

[0961]

[0962] This compound was prepared by the same methodology described forExample 13 with piperazine substituted for N-methylethylenediamine.ES-MS: (M+H)⁺457.

Example 20

[0963]

[0964] This compound was prepared by the same methodology described forExample 13 with N-methylpiperazine substituted forN-methylethylenediamine. ES-MS: (M+H)⁺471.

Example 21

[0965]

[0966] This compound was prepared by the same methodology described forExample 13 with ammonium acetate substituted forN-methylethylenediamine. ES-MS: (M+H)⁺388.

Example 22

[0967]

[0968] Step 1. 2-Fluoro-4-iodoaniline (5.0 g, 21 mmol) was dissolved in20 mL dry DMF. To it were added CuCN (3.8 g, 42 mmol) and catalyticamount of CuI (200 mg). The slurry was refluxed for 1 hour. Diluted withEtOAc. Filtered through celite. Concentrated in vacuuo to yield solid4-amino-3-fluorobenzonitrile (2.9 g, 100%). ES-MS: (M+H)⁺137.

[0969] Step 2. The preparation of3-methyl-1-(3-fluoro-2-naphthyl)-1H-pyrazolecarboxylic acid was the sameas that in Step 1 of Example 4. This acid (270 mg, 1.0 mmol),4-amino-3-fluorobenzonitrile (272 mg, 2.0 mmol) and DMAP (10 mg) weredissolved in 15 mL pyridine. The solution was stirred at 0° C. To it wasadded POCl₃ (380 μL, is 4.0 mmol). The mixture was stirred for 1 hour.The reaction was then quenched with ice chips. It was diluted withEtOAc. The organic phase was washed with brine (×2). It was dried,concentrated and purified with flash column to afford the couplingproduct (350 mg, 97%). Rf 0.77 (7:3 EtOAc:hexane). ES-MS: (M+H)⁺389.

[0970] Step 3. The above-prepared nitrile (30 mg, 0.077 mmol) wasdissolved in 10 mL dry methanol. It was chilled and stirred in an icebath. To this solution was bubbled dry HCl gas via a long needle tillsaturation reached (indicated by a blown-up balloon attached on the topof the reaction flask). The resulting solution was stirred overnight.ES-MS: (M+H)⁺421. The solvent was removed in vacuuo. The residue waspumped to dryness. The solid was dissolved in 5 mL dry methanol. To itwas added anhydrous N-methylethylenediamine (0.5 mL). The mixture wasrefluxed for 1 hour, concentrated and loaded on prep HPLC to afford thetitle compound in 80% yield. ES-MS: (M+H)⁺446.

Example 23

[0971]

[0972] This compound was prepared by the same methodology described forExample 22 with pyrrolidine substituted for N-methylethylenediamine.ES-MS: (M+H)⁺460.

Example 24

[0973]

[0974] This compound was prepared by the same methodology described forExample 22 with piperidine substituted for N-methylethylenediamine.ES-MS: (M+H)⁺474.

Example 25

[0975]

[0976] This compound was prepared by the same methodology described forExample 22 with hexamethyleneimine substituted forN-methylethylenediamine. ES-MS: (M+H)⁺488.

Example 26

[0977]

[0978] This compound was prepared by the same methodology described forExample 22 with morpholine substituted for N-methylethylenediamine.ES-MS: (M+H)⁺476.

Example 27

[0979]

[0980] This compound was prepared by the same methodology described forExample 22 with ammonium acetate substituted forN-methylethylenediamine. ES-MS: (M+H)⁺406.

Example 28

[0981]

[0982] Step 1. The preparation of3-methyl-1-(3-fluoro-2-naphthyl)-1H-pyrazolecarboxylic acid was the sameas that in Step 1 of Example 4. This acid (50 mg, 0.18 mmol),4-amino-2,5-difluorobenzonitrile (57 mg, 0.36 mmol) and DMAP (5 mg) weredissolved in 8 mL pyridine. The solution was stirred at 0° C. To it wasadded POCl₃ (70 μL, 0.74 mmol). The mixture was stirred for 1 hour. Thereaction was then quenched with ice chips. It was diluted with EtOAc.The organic phase was washed with brine (×2). It was dried, concentratedand purified with flash column to afford the coupling product (70 mg,93%). Rf 0.69 (7:3 EtOAc:hexane). ES-MS: (M+H)⁺407.

[0983] Step 2. The above-prepared nitrile (30 mg, 0.074 mmol) wasdissolved in 10 mL dry methanol. It was chilled and stirred in an icebath. To this solution was bubbled dry HCl gas via a long needle tillsaturation reached (indicated by a blown-up balloon attached on the topof the reaction flask). The resulting solution was stirred overnight.ES-MS: (M+H)⁺439. The solvent was removed in vacuuo. The residue waspumped to dryness. The solid was dissolved in 5 mL dry methanol. To itwas added anhydrous N-methylethylenediamine (0.5 mL). The mixture wasrefluxed for 1 hour, concentrated and loaded on prep UPLC to afford thetitle compound in 80% yield. ES-MS: (M+H)⁺464.

Example 29

[0984]

[0985] This compound was prepared by the same methodology described forExample 28 with pyrrolidine substituted for N-methylethylenediamine.ES-MS: (M+H)⁻478.

Example 30

[0986]

[0987] This compound was prepared by the same methodology described forExample 28 with ammonium acetate substituted forN-methylethylenediamine. ES-MS: (M+H)⁺424.

Example 31

[0988]

[0989] This compound was prepared by the same methodology from Step 3 toStep 5 described for Example 3 with 3-chloro-2-naphthylamine substitutedfor 3-fluoro-2-naphthylamine. ES-MS: (M+H)⁺517.

Example 32

[0990]

[0991] This compound was prepared by the same methodology from Step 3 toStep 5 described for Example 3 with 3-bromo-2-naphthylamine substitutedfor 3-fluoro-2-naphthylamine. ES-MS: (M+H)⁺561, 563 (Br pattern).

Example 33

[0992]

[0993] This compound was prepared by the same methodology from Step 3 toStep 5 described for Example 3 with 3-hydroxy-2-naphthylaminesubstituted for 3-fluoro-2-naphthylamine. ES-MS: (M+H)⁺499.

Example 34

[0994]

[0995] Step 1. The synthesis of ethyl3-methyl-1-(3-bromo-2-naphthyl)-1H-pyrazole-carboxylate followed thesame methodology described for Step 3 of Example 3 with commercial with3-bromo-2-naphthylamine substituted for 3-fluoro-2-naphthylamine. Yield60%. Rf 0.42 (1:3 EtOAc:hexane). ES-MS: (M+H)⁺359, 361 (Br pattern).

[0996] Step 2. The above-prepared bromide (370 mg, 1.0 mmol) wasdissolved in 3 mL dry DMF. To it were added CuCN (180 mg, 2.0 mmol) andCul (20 mg). The slurry mixture was refluxed for 2 hours. It was dilutedwith EtOAc. Filtered through celite. Concentrated and purified by flashcolumn to yield of ethyl3-methyl-1-(3-cyano-2-naphthyl)-1H-pyrazole-carboxylate (220 mg, 70%).Rf 0.48 (1:2 EtOAc:hexane).). ES-MS: (M+H)⁺306.

[0997] Step 3. To a solution of2′-N-tert-butylaminosulfonyl-[1,1′]-biphenyl-4-ylamine (164 mg, 0.54mmol) in 2 mL dry DCM was added trimethylaluminum (2.0M in hexane, 1.1mL, 2.2 mmol). The mixture was stirred for 20 minutes. Theabove-prepared ester (137 mg, 0.45 mmol) was dissolved in 6 mL dry DCMand added into the aluminum mixture. The reaction was stirred at roomtemperature for overnight and quenched using saturated Rochelle's saltaq solution. It was extracted with CHCl₃ (×3). The organic phases werecombined, dried, concentrated and purified with flash column to yield3-methyl-1-(3-cyano-2-naphthyl)-1H-pyrazole-5-(N-(2′-N-tert-butylaminosulfonyl-[1,1′]-biphen-4-yl))carboxyamide(170 mg, 67%). Rf 0.40 (1:1 EtOAc:hexane). ES-MS: (M+H)⁺564.

[0998] Step 4. The above-prepared compound (30 mg, 0.05 mmol) wasdissolved in 5 mL dry DCM. At 0° C., to it was added BF₃.OEt₂ (62 μL,0.5 mmol) dropwise. The mixture was stirred overnight. Extra 1.0 mmolBF₃.OEt₂ was added in small portions at room temperature the next day.After another overnight, deprotection was about 70% complete. Themixture was loaded on a short flash column for separation. The titleproduct was purified using prep HPLC (55% yield). ES-MS: (M+H)⁺508.

Example 35

[0999]

[1000] Step 1. The synthesis of3-methyl-1-(3-cyano-2-naphthyl)-1H-pyrazole-5-(N-(2′-N-tert-butylaminosulfonyl-[1,1′]-biphen-4-yl))carboxyamidefollowed the same procedure of Step 3 for Example 34.

[1001] Step 2. The above-prepared compound (30 mg, 0.05 mmol) was placedin 3 mL TFA and refluxed for 1 hour. After concentration, it waspurified with prep HPLC to yield the title compound (85%). ES-MS:(M+H)⁺526.

Example 36

[1002]

[1003] This compound was prepared by the same methodology described forExample 34 with 2′-N-tert-butylamino sulfonyl-3-fluoro-[1,1′]-biphenyl-4-ylamine substituted for2′N-tert-butylaminosulfonyl-[1,1′]-biphenyl-4-yl amine. ES-MS:(M+H)⁺526.

Example 37

[1004]

[1005] This compound was prepared by the same methodology described forExample 35 with 2′-N-tert-butylaminosulfonyl-3-fluoro-[1,1′]-biphenyl-4-ylamine substituted for2′-N-tert-butylaminosulfonyl-[1,1′]-biphenyl-4-ylamine. ES-MS:(M+H)⁺544.

Example 38

[1006]

[1007] Step 1. The synthesis of ethyl3-methyl-1-(3-cyano-2-naphthyl)-1H-pyrazole-carboxylate followed thesame procedure of Step 2 for Example 34.

[1008] Step 2. The above-prepared ester (930 mg, 3.0 mmol) was dissolvedin 20 mL methanol. To it were added LiOH.H₂O (256 mg, 6.0 mmol) and 10mL water. The mixture was stirred for 3 hours at room temperature.Methanol was removed in vacuuo. The residue was carefully acidified with1N HCl till pH 1. It was extracted with EtOAc (×4). The organic phaseswere combined, dried and evaporated in vacuuo till dryness to give3-methyl-1-(3-cyano-2-naphthyl)-1H-pyrazole-5-carboxylic acid (720 mg,85%). ES-MS: (M+H)⁺278.

[1009] Step 3. The mixture of the above-prepared acid (110 mg, 0.40mmol), 2′-N-tert-butylaminosulfonyl-3-chloro-[1,1′]-biphenyl-4-ylamine(0.21 g, 0.60 mmol), DMAP (5 mg) were dissolved in 5 mL pyridine andstirred at 0° C. To it was added POCl₃ (120 μL, 1.2 mmol). The mixturewas stirred for 2.5 hours and quenched with ice chips. It was dilutedwith EtOAc, washed with brine (×2), dried, concentrated and purifiedwith flash column to give3-methyl-1-(3-cyano-2-naphthyl)-1H-pyrazole-5-(N-(2′-N-tert-butylaminosulfonyl-3-chloro-[1,1′]-biphen-4-yl))carboxyamide(240 mg, 95%). Rf 0.65 (1:1 EtOAc:hexane). ES-MS: (M+H)⁺598.

[1010] Step 4. The above-prepared compound (30 mg, 0.05 mmot) wasdissolved in 5 mL io dry DCM. At 0° C., to it was added BF₃.OEt₂ (62 μL,0.5 mmol) dropwise. The mixture was stirred overnight. Extra 1.0 mmolBF₃.OEt₂ was added in small portions at room temperature the next day.After another overnight, deprotection was about 70% complete. Themixture was loaded on a short flash column for separation. The titleproduct was purified using prep HPLC (52% yield). ES-MS: (M+H)⁺542.

Example 39

[1011]

[1012] Step 1. The synthesis of3-methyl-1-(3-cyano-2-naphthyl)-1H-pyrazole-5-(N-(2′-N-tert-butylaminosulfonyl-3-chloro-[1,1′]-biphen-4-yl))carboxyamidefollowed the same procedure of Step 3 for Example 38.

[1013] Step 2. The above-prepared compound (30 mg, 0.05 mmol) was placedin 3 mL TFA and refluxed for 1 hour. After concentration, it waspurified with prep HPLC to yield the title compound (85%). ES-MS:(M+H)⁺560.

Example 40

[1014]

[1015] This compound was prepared by the same methodology described forExample 38 with2′-N-tert-butylaminosulfonyl-3-bromo-[1,1′]-biphenyl-4-ylaminesubstituted for2′-N-tert-butylaminosulfonyl-3-chloro-[1,1′]-biphenyl-4-ylamine. ES-MS:(M+H)⁺586, 588 (Br pattern).

Example 41

[1016]

[1017] This compound was prepared by the same methodology described forExample 39 with2′-N-tert-butylaminosulfonyl-3-bromo-[1,1′]-biphenyl-4-ylaminesubstituted for2′-N-tert-butylaminosulfonyl-3-chloro-[1,1′]-biphenyl-4-ylamine. ES-MS:(M+H)⁺604, 606 (Br pattern).

Example 42

[1018]

[1019] This compound was prepared by the same methodology described forExample 3 8 with 2-amino-5-(2-(N-tert-butylaminosulfonyl)phenyl)pyridinesubstituted for2′-N-tert-butylaminosulfonyl-3-chloro-[1,1′]-biphenyl-4-ylamine. ES-MS:(M+H)⁺509.

Example 43

[1020]

[1021] This compound was prepared by the same methodology described forExample 39 with 2-amino-5(2-(N-tert-butylamino sulfonyl)phenyl)pyridmnesubstituted for 2′-N-tert-butyl aminosulfonyl-3-chioro-[1,1′]-biphenyl-4-ylamine. ES-MS: (M+H)⁺527.

Example 44

[1022]

[1023] This compound was prepared by the same methodology described forExample 38 with2-amino-5-(2-(N-tert-butylaminosulfonyl)phenyl)pyrimidine substitutedfor 2′-N-tert-butylaminosulfonyl-3-chloro-[1,1 ′]-biphenyl-4-ylamine.ES-MS: (M+H)⁺510.

Example 45

[1024]

[1025] This compound was prepared by the same methodology described forExample 39 with2-amino-5-(2-(N-tert-butylaminosulfonyl)phenyl)pyrimidine substitutedfor 2′-N-tert-butylaminosulfonyl-3-chloro-[1,1′]-biphenyl-4-ylamine.ES-MS: (M+H)⁺528.

Examle 46

[1026]

[1027] Step 1. To a solution of 4-nitroaniline (1.0 g, 6.7 mmol) in 50mL anhydrous ethanol at 0° C. was bubbled dry HCl gas via a long needletill saturation reached. The resulting solution was stirred overnight.The solvent was removed in vacuuo. The residue was pumped to dryness. Itwas dissolved in 50 mL anhydrous ethanol. To it was added 2 mLN-methylethylenediamine. The mixture was refluxed for 1 hour andevaporated in vacuuo to give the 1-methyl-2-(4-nitrophenyl)-2-imidazoline HCl salt in 90% yield. ES-MS: (M+H)⁺206.

[1028] Step 2. To a solution of the above-prepared nitro compound (500mg, 2.4 mmol) in 4 mL 4N HCl and 50 mL methanol was added 10% Pd/C (50mg). The mixture was stirred for 2 hours under a hydrogen balloon. Itwas filtered through celite and concentrated in vacuuo to give the4-(1-methyl-2-imidazolin-2-yl)aniline HCl salt in 90% yield. ES-MS:(M+H)⁺176.

[1029] Step 3. To a solution of the above-prepared amine (40 mg, 0.22mmol), 3-methyl-1-(3-cyano-2-naphthyl)-1H-pyrazole-5-carboxylic acid (15mg, 0.054 mmol, see Step 2, Example 38), DMAP (2 mg) in 2 mL pyridine at0° C. was added POCl₃ (20 μL, 0.22 mmol). The mixture was stirred for 2hours. It was concentrated in vacuuo and loaded on prep HPLC to affordthe title compound in 60% yield. ES-MS: (M+H)⁺435.

Example 47

[1030]

[1031] The title compound in Example 46 (10 mg) was placed in TFA. Itwas refluxed for 1 hour and subjected on prep HPLC purification toafford the title compound in 85% yield. ES-MS: (M+H)⁺453.

Example 48

[1032]

[1033] Step 1. To a solution of 2-fluoro-4-nitroaniline (300 mg, 2.2mmol) in 20 mL anhydrous methanol at 0° C. was bubbled dry HCl gas via along needle till saturation reached. The resulting solution was stirredovernight. The solvent was removed in vacuuo. The residue was pumped todryness. It was dissolved in 10 mL anhydrous methanol. To it was added 1mL N-methylethylenediamine. The mixture was refluxed for 1 hour andevaporated in vacuuo to give the1-methyl-2-(2-fluoro-4-nitrophenyl)-2-imidazoline HCl salt in 90% yield.ES-MS: (M+H)⁺224.

[1034] Step 2. To a solution of the above-prepared nitro compound in 2mL 4N HCl and 25 mL methanol was added 10% Pd/C (20 mg). The mixture wasstirred for 2 hours under a hydrogen balloon. It was filtered throughcelite and concentrated in vacuuo to give the2-fluoro-4-(1-methyl-2-imidazolin-2-yl)aniline HCl salt in 90% yield.ES-MS: (M+H)⁺194.

[1035] Step 3. To a solution of the above-prepared amine (100 mg, 0.51mmol) in 2 mL DCM was added trimethylaluminum (2.0M in hexane, 2 mL, 4.0mmol). The mixture was stirred for 20 minutes. Ethyl3-methyl-1-(3-cyano-2-naphthyl)-1H-pyrazole-carboxylate (76 mg, 0.25mmol, see Step 2 of Example 34) was dissolved in 2 mL DCM and added intothe reaction flask. The mixture was stirred for 2 days at roomtemperature. It was quenched with saturated Rochelle's salt aq solutionand extracted with CHCl₃ (×4). The organic phases were combined, dried,concentrated and purifed with prep HPLC to yield the title compound(55%).. ES-MS: (M+H)⁺453.

Example 49

[1036]

[1037] The title compound in Example 48 (10 mg) was placed in TFA. Itwas refluxed for 1 hour and subjected on prep BPLC purification toafford the title compound in 85% yield. ES-MS: (M+H)⁺471.

Example 50

[1038]

[1039] Step 1. Compound3-methyl-1-(3-cyano-2-naphthyl)-1H-pyrazole-5-(N-(2′-N-tert-butylaminosulfonyl-[1,1′]-biphen-4-yl))carboxyamidewas prepared by the same procedure shown in Step 3 of Example 34.

[1040] Step 2. The above-prepared compound (70 mg, 0.12 mmol) wasdissolved in 2 mL dry DMF. At 0° C., to it were added sodium borohydride(36 mg, 0.96 mmol) and CoCl₂ (32 mg, 0.24 mmol. It was stirred for 2days. Diluted with EtOAc and stirred for 1 hour. The mixture wasfiltered through celite. The filtrate was evaporated to give crude3-methyl-1-(3-aminomethyl-2-naphthyl)-1H-pyrazole-5-(N-(2′-N-tert-butylaminosulfonyl-[1,1′]-biphen-4-yl))carboxyamide.ES-MS: (M+H)⁺568.

[1041] Step 3. The above-prepared crude compound was taken into 3 mLTFA. The mixture was stirred for 1 hour at 60° C. The mixture wasevaporated and subjected on prep BPLC to isolate the title compound (35%yield). ES-MS: (M+H)⁺512.

Example 51

[1042]

[1043] Step 1. Compound3-methyl-1-(3-cyano-2-naphthyl)-1H-pyrazole-5-(N-(2′-N-tert-butylaminosulfonyl-3-fluoro-[1,1′]-biphen-4-yl))carboxyamidewas prepared by the same methodology shown in Step 3 of Example 34, with2′-N-tert-butylaminosulfonyl-3-fluoro-[1,1′]-biphenyl-4-ylaminesubstituted for 2′-N-tert-butylaminosulfonyl-[1,1′]-biphenyl-4-ylamine.ES-MS: (M+H)⁺582.

[1044] Step 2. To a solution of the above-prepared compound (77 mg, 0.13mmol) in 3 mL anhydrous methanol and 3 mL anhydrous EtOAc at −20° C. wasbubbled dry HCl gas via a long needle till saturation reached. Themixture was stirred for overnight. The solvent was removed in vacuuo.The dry residue was dissolved in 5 mL anhydrous methanol. To it wasadded 50 mg ammonium acetate. The mixture was refluxed for 2.5 hours. Itwas subjected on prep UPLC to isolate the title compound (55% yield).ES-MS: (M+H)⁺543.

Example 52

[1045]

[1046] Step 1. 3-Amino-2-naphthoic acid (5.8 g, 31 mmol) was placed in50 mL concentrate HCl. The slurry was vigorously stirred at 0° C. To itwas added dropwise a cold solution of sodium nitrite (2.35 g, 34 mmol,in 14 mL water). After completion, the mixture was stirred for 40minutes at 0° C. Under vigorously stirring, a cold solution ofSnCl₂.2H₂O (21 g, 93 mmol, in 30 mL concentrate HCl) was added dropwise.The mixture was stirred for 30 minutes and chilled in ice bath. Thecrude 3-carboxyl-2-naphthylhydrazine was collected with a Buchner funneland pumped to dryness in vacuuo.

[1047] Step 2. The crude hydrazine prepared above was taken into 60 mLglacial acetic acid and 30 mL THF. To it was added ethyl2—N-(methoxy)imino-4-oxopentanoate (2.6 g, 14 mmol). The mixture wasrefluxed for overnight. The solvent was removed in vacuuo. The residuewas dissolved in EtOAc and washed with brine (×2). The organic phase wasdried, concentrated and purified with flash column to yield ethyl3-methyl-1-(3-carboxyl-2-naphthyl)-1H-pyrazole-5-carboxylate (4.1 g,90%). Rf 0.15 (1:1 EtOAc:hexane). ES-MS: (M+H)⁺325.

[1048] Step 3. To a solution of2′-N-tert-butylaminosulfonyl-[1,1′]-biphenyt-4-ylamine (36 mg, 0.12mmol) in 1 mL dry DCM was added trimethylaluminum (2.0M in hexane, 0.5mL, 1.0 mmol). The mixture was stirred for 20 minutes. Theabove-prepared ester (38 mg, 0.12 mmol) was dissolved in 3 mL dry DCMand added into the aluminum mixture. The reaction was stirred at roomtemperature for overnight and quenched using saturated Rochelle's saltaq solution. It was extracted with CHCl₃ (×3). The organic phases werecombined, dried, concentrated and purified with flash column to yieldthe coupling product (60%). ES-MS: (M+H)⁺583.

[1049] Step 4. The above-prepared compound (15 mg) was placed in 3 mLTFA and stirred overnight. It was concentrated and purified with prepHPLC to afford the title compound in 90% yield. ES-MS: (M+H)⁺527.

Example 53

[1050]

[1051] This compound was prepared by the same methodology described forExample 52 with 2′-N-tert-butylaminosulfonyl-3-fluoro-[1,1′]-biphenyl-4-ylamine substituted for2′-N-tert-butylaminosulfonyl-[1,1′]-biphenyl-4-yl amine. ES-MS:(M+H)⁺545.

Example 54

[1052]

[1053] This compound was prepared by the same methodology described forExample 52 with 2′-N-tert-butylaminosulfonyl-3-chloro-[1,1′]-biplienyl-4-ylamine substituted for2′-N-tert-butylamino sulfonyl-[1,1′]-biphenyl-4-ylamine. ES-MS:(M+Hl)⁺561.

Example 55

[1054]

[1055] This compound was prepared by the same methodology described forExample 52 with2′-N-tert-butylaminosulfonyl-3-bromo-[1,1′]-biphenyl-4-ylaminesubstituted for 2′-N-tert-butylaminosulfonyl-[1,1′]-biphenyl-4-ylamine.ES-MS: (M+H)⁺605 and 607 (Br pattern).

Example 56

[1056]

[1057] The title compound of Example 52 (14 mg, 0.027 mmol) wasdissolved in 2 mL anhydrous THF. To it was added BH₃ (1M, 0.11 mL, 0.11mmol) at 0° C. The mixture was stirred for 1 hour and quenched withacetic acid. The mixture was directly pufied with prep HPLC to yield thetitle compound in 55% yield. ES-MS: (M+H)⁺513.

Example 57

[1058]

[1059] The title compound of Example 52 (5 mg, 0.01 mmol) was dissolvedin 1 mL anhydrous THF. To it was added TMSCH₂N₂ (2M, 0.01 mL, 0.02 mmol)at 0° C. The mixture was stirred for 1 hour at room temperature andquenched with TFA. The mixture was directly purified with prep BPLC toyield the title compound in 65% yield. ES-MS: (M+H)⁺541.

Example 58

[1060]

[1061] Step 1. Compound ethyl3-methyl-1-(3-fluoro-2-naphthyl)-1H-pyrazole-5-carboxylate was preparedusing the procedure described in Step 3 of Example 3.

[1062] Step 2. The above-prepared fluoride (10.3 g, 34 mmol) wasdissolved in 100 mL anhydrous DMSO. To it was added sodium thiomethoxide(27 g, 340 mmol). The mixture was stirred at 100° C. for half an hour.The reaction was quenched with acetic acid. The mixture was evaporatedto remove acetic acid, and was acidified using 5N HCl till pH 1 undervigorously stirring. It was extracted with EtOAc(×5). The organic phaseswere combined, dried and evaporated in vacuuo to afford crude3-methyl-1-(3-methylthio-2-naphthyl)-1H-pyrazole-5-carboxylic acid inover 90% yield. ES-MS: (M+H)⁺299.

[1063] Step 3. The above-prepared crude acid was dissolved in 150 mLanhydrous ethanol. To it was added pTSA (3.3 g). The mixture wasrefluxed for 4 days till the esterification was over 95% complete. Thesolvent was removed in vacuuo. The residue was dissolved in EtOAc,washed with brine (×3), dried and purified by a short silica column toafford ethyl3-methyl-1-(3-methylthio-2-naphthyl)-1H-pyrazole-5-carboxylate in over80% yield. ES-MS: (M+H)⁺327.

[1064] Step 4. The above-prepared ester (4.95 g, 15 mmol) was dissolvedin 150 mL DCM. At 0° C., to the vigorously stirred solution was addedMCPBA (11 g, 38 mmol) in small portions over 20 minutes. The reactionwas allowed for 1 hour and diluted with CHCl₃. It was washed with NaHCO₃saturated aq solution (×3), dried, concentrated and purified with flashcolumn to give ethyl3-methyl-1-(3-methylsulfonyl-2-naphthyl)-1H-pyrazole-5-carboxylate (3.49g, 65%). Rf 0.52 (1:1 EtOAc:hexane). ES-MS: (M+H)⁺359.

[1065] Step 5. To a solution of2′-N-tert-butylaminosulfonyl-[1,1′]-biphenyl-4-ylamine (21 mg, 0.068mmol) in 1 mL dry DCM was added trimethylaluminum (2.0M in hexane, 0.14mL, 0.28 mmol). The mixture was stirred for 20 minutes. Theabove-prepared ester (16 mg, 0.045 mmol) in Step 4 was dissolved in 4 mLdry DCM and added into the aluminum mixture. The reaction was stirred atroom temperature for overnight and quenched using saturated Rochelle'ssalt aq solution. It was extracted with CHCl₃ (×3). The organic phaseswere combined, dried, concentrated and purified with flash column toyield the coupling product (52%). Rf 0.17 (1:1 EtOAc: Hexane). ES-MS:(M+H)⁺617.

[1066] Step 6. The above-prepared compound was dissolved in 2 mLacetonitrile and 2 mL TFA. The mixture was stirred for 1 hour at 70 C.The mixture was evaporated and purified with prep BPLC to afford thetitle compound in 90% yield. ES-MS: (M+H)⁺561.

Example 59

[1067]

[1068] Step 1. The synthesis of ethyl3-methyl-1-(3-methylsulfonyl-2-naphthyl)-1H-pyrazole-5-carboxylate wasthe same as that described in Step 4 of Example 58.

[1069] Step 2. The above-prepared ester (3.4 g, 9.7 mmol) was dissolvedin 20 mL methanol. To it were added LiOH.H₂O (0.82 g, 19.5 mmol) and 10mL water. The mixture was stirred at room temperature for overnight. Thesolvent was evaporated. The residue was acidified with 1N HCl till pH 1.The mixture was extracted with EtOAc (×4). The organic phases werecombined, dried, evaporated to dryness to afford3-methyl-1-(3-methylulfonyl-2-naphthyl)-1H-pyrazole-5-carboxylic acid(3.24 g, 99%). ES-MS: (M+H)⁺331.

[1070] Step 3. The above-prepared acid (102 mg, 0.31 mmol),2′-N-tert-butylaminosulfonyl-3-fluoro-[1,1′]-biphenyl-4-ylamine (150 mg,0.46 mmol), DMAP (10 mg) were dissolved in 3 mL pyridine. To thisstirred solution at 0° C. was added POCl₃ (87 μL, 0.93 mmol). Themixture was stirred for 2 hours and quenched with ice chips. It wasdiluted with EtOAc , washed with brine (×2), dried, concentrated andpurified with flash column to give the coupling product (130 mg, 66%).Rf 0.29 (1:1 EtOAc:hexane). MS: (M+H)⁺6.5.

[1071] Step 4. The above-prepared compound (100 mg) was taken into 5 mLTFA and stirred at room temperature for overnight. After evaporation,the mixture was subjected on prep EPLC to isolate the title compound(90%). MS: (M+H)⁺579.

Example 60

[1072]

[1073] This compound was prepared by the same methodology described forExample 59 with 2′-N-tert-butylaminosulfonyl-3-chloro-[1,1′]-biphenyl-4-ylamine substituted for2′-N-tert-butylaminosulfonyl-3-fluoro-[1,1′]-biphenyl-4-ylamine. ES-MS:(M+H)⁺595.

Example 61

[1074]

[1075] This compound was prepared by the same methodology described forExample 59 with 2′-N-tert-butylaminosulfonyl-3-bromo-[1,1′]-biphenyl-4-ylamine substituted for2′-N-tert-butylaminosulfonyl-3-fluoro-[1,1′]-biphenyl-4-ylamine. ES-MS:(M+H)⁺639, 641 (Br pattern).

Example 62

[1076]

[1077] This compound was prepared by the same methodology described forExample 59 with 2-amino-5-(2-(N-tert-butylaminosulfonyl)phenyl)pyridinesubstituted for 2′-N-tert-butylaminosulfonyl-3-fluoro-[1,1′]-biphenyl-4-ylamine. ES-MS: (M+H)⁺562.

Example 63

[1078]

[1079] This compound was prepared by the same methodology described forExample 59 with2-amino-5-(2-(N-tert-butylaminosulfonyl)phenyl)pyrimidine substitutedfor 2′-N-tert-butylaminosulfonyl-3-fluoro-[1,1′]-biplienyl-4-ylamine.ES-MS: (M+H)⁺563.

Example 64

[1080]

[1081] This compound was prepared by the same methodology described forExample 59 with for 2′-methylsulfonyl-[1,1 ′]-biphenyl-4-ylaminesubstituted for2′-N-tert-butylaminosulfonyl-3-fluoro-[1,1′]-biphenyl-4-ylamine, withoutthe final TFA treatment. ES-MS: (M+H)⁺560.

Example 65

[1082]

[1083] This compound was prepared by the same methodology described forExample 59 with for 2′-cyano-[1, 1′]-biphenyl-4-ylamine substituted for2′-N-tert-butylaminosulfonyl-3-fluoro-[1,1′]-biphenyl-4-ylamine, withoutthe final TFA treatment. ES-MS: (M+H)⁺507.

Example 66

[1084]

[1085] The title compound of Example 65 (55 mg, 0.11 mmol) was dissolvedin 2 mL anhydrous DMF. To this stirred solution at 0° C. were addedsodium borohydride (33 mg, 0.88 mmol) and CoCl₂ (30 mg, 0.22 mmol). Thereaction was allowed for 2 hours and quenched with acetic acid. Themixture was evaporated, diluted with EtOAc, and washed with NaHCO₃ aqsolution. The organic phase was dried, evaporated and purified with prepKPLC to afford the title compound in 55% yield. ES-MS: (M+H)⁺511.

Example 67

[1086]

[1087] This compound was prepared by the same methodology described forExample 59 with for 2′-(N-dimethylaminomethyl)-[1,1′]-biphenyl-4-ylamine substituted for2′-N-tert-butylaminosulfonyl-3-fluoro-[1,1′]-biphenyl-4-ylamine, withoutthe final TFA treatment. ES-MS: (M+H)⁺539.

Example 68

[1088]

[1089] This compound was prepared by the same methodology described forExample 59 with for 3′-(N-tert-Boc-aminomethyl)-[1,1′]-biphenyl-4-ylamine substituted for2′-N-tert-butylaminosulfonyl-3-fluoro-[1,1′]-biphenyl-4-ylamine. ES-MS:(M+H)⁺511.

Example 69

[1090]

[1091] This compound was prepared by the same methodology described forExample 59 with for 1-(4-Aminophenyl)-4-methylpiperazine hydrochlordesubstituted for 2′-N-tert-butylaminosulfonyl-3-fluoro-[1,1′]-biphenyl-4-ylamine, without the final TFA treatment. ES-MS:(M+H)⁺504.

Example 70

[1092]

[1093] This compound was prepared by the same methodology described forExample 59 with for 1-(N-methylpiperidin-4-yl)-piperazine substitutedfor 2′-N-tert-butylaminosulfonyl-3-fluoro-[1,1 ′]-biphenyl-4-ylamine,without the final TFA treatment. ES-MS: (M+H)⁺496.

Example 71

[1094]

[1095] This compound was prepared by the same methodology described forExample 59 with for 1-(4-pyridyl)-piperazine substituted for2′-N-tert-butylamino sulfonyl-3-fluoro-[1,1′]-biphenyl-4-ylamine,without the final TFA treatment. ES-MS: (M+H)⁺476.

Example 72

[1096]

[1097] This compound was prepared by the same methodology described forExample 59 with for 4-(N-pyrrolidinylcarbonyl)-aniline substituted for2′-N-tert-butylaminosulfonyl-3-fluoro-[1,1′]-biphenyl-4-ylamine, withoutthe final TFA treatment. ES-MS: (M+H)⁺503.

Example 73

[1098]

[1099] Step 1. The synthesis of3-methyl-1-(3-methylsulfonyl-2-naphthyl)-1H-pyrazole-5-carboxylic acidwas the same as that described in Step 2 of Example 59.

[1100] Step 2. The above-prepared acid (200 mg, 0.61 mmol),4-aminobenzonitrile (108 mg, 0.91 mmol) and DMAP (10 mg) were dissolvedin 6 mL pyridine. The solution was stirred at 0° C. To it was addedPOCl₃ (170 μL, 1.8 mmol). The mixture was stirred for 1 hour. Thereaction was then quenched with ice chips. It was diluted with EtOAc.The organic phase was washed with brine (×2). It was dried, concentratedand purified with flash column to afford the coupling product (250 mg,95%). Rf 0.20 (1:1 EtOAc:hexane). ES-MS: (M+H)⁺431.

[1101] Step 3. The above-prepared nitrile (70 mg, 0.16 mmol) wasdissolved in 6 mL dry methanol. It was chilled and stirred in an icebath. To this solution was bubbled dry HCl gas via a long needle tillsaturation reached (indicated by a blown-up balloon attached on the topof the reaction flask). The resulting solution was stirred overnight.ES-MS: (M+H)⁺463. The solvent was removed in vacuuo. The residue waspumped to dryness. The solid was dissolved in 6 mL dry methanol. To itwas added anhydrous N-methylethylenediamine (0.5 mL). The mixture wasrefluxed for 1 hour, concentrated and loaded on prep HPLC to afford thetitle compound in 80% yield. ES-MS: (M+H)⁺488.

Example 74

[1102]

[1103] This compound was prepared by the same methodology described forExample 73 with pyrrolidine substituted for N-methylethylenediamine.ES-MS: (M+H)⁺502.

Example 75

[1104]

[1105] This compound was prepared by the same methodology described forExample 73 with morpholine substituted for N-methylethylenediamine.ES-MS: (M+H)⁺518.

Example 76

[1106]

[1107] This compound was prepared by the same methodology described forExample 73 with N-methylpiperazine substituted forN-methylethylenediamine. ES-MS: (M+H)⁺531.

Example 77

[1108]

[1109] This compound was prepared by the same methodology described forExample 73 with 4-amino-3-fluorobenzonitrile (preparation described inStep 1 of Example 22) substituted for 4-aminobenzonitrile. ES-MS:(M+H)⁺506.

Example 78

[1110]

[1111] This compound was prepared by the same methodology described forExample 73 with 4-amino-3-fluorobenzonitrile substituted for4-aminobenzoniteie, and with N-methyl-1,3-propanediamine substituted forN-methylethylenediamine. ES-MS: (M+H)⁺520.

Example 79

[1112]

[1113] This compound was prepared by the same methodology described forExample 73 with 4-amino-3-fluorobenzonitrile substituted for4-aininobenzonitrile, and with pyrrolidine substituted forN-methylethylenediamine. ES-MS: (M+H)⁺520.

Example 80

[1114]

[1115] This compound was prepared by the same methodology described forExample 73 with 4-amino-3-fluorobenzonitrile substituted for4-aminobenzorntrle, and with piperidine substituted forN-methylethylenediamine. ES-MS: (M+H)⁺534.

Example 81

[1116]

[1117] This compound was prepared by the same methodology described forExample 73 with 4-amino-3-fluorobenzonitrile substituted for4-aminobenzonitrile, and with dimethylamine (2M solution in THF)substituted for N-methylethylenediamine. ES-MS: (M+H)⁺494.

Example 82

[1118]

[1119] This compound was prepared by the same methodology described forExample 73 with 4-amino-3-fluorobenzonitrile substituted for4-aminobenzonitrle, and with ammonium acetate substituted forN-methylethylenediamine. ES-MS: (M+H)⁺466.

Example 83

[1120]

[1121] Step 1. To a solution of 2-bromo-6-methoxynaphthalene (2.0 g, 8.4mmol) in 20 mL anhydrous THF at −78° C. was added BuLi (1.6M, 7.9 mL,12.6 mmol) dropwise with a syringe. The mixture was stirred for 30minutes, then to it was added triisopropyl borane (2.34 mL, 10.1 mmol)dropwise. The dry ice bath was removed. The reaction mixture was allowedto warm up to room temperature. After 15 hours, THF was mostly removedin vacuuo. To the residue was added 40 mL 3M HCl. The mixture wasstirred at room temperature for 8 hours. Ether was used to extract theproduct (×3). The organic phases were combined, dried, concentrated invacuuo and pumped to dryness to afford 6-methoxy-2-naphthylboronic acid(75% yield) as a white solid. Rf 0.34 (1:1 EtOAc:hexane).

[1122] Step 2. To a solution of the above-prepared boronic acid (0.84 g,3.2 mmol) and ethyl 3-methylpyrazole-5-carboxylate (0.49 g, 3.2 mmol) in20 mL dry DCM were added pyridine (0.77 mL, 9.5 mmol) and anhydrouspowder of copper(II) acetate (1.15 g, 6.3 mmol). Some activatedmolecular sieve powder was added afterwards. The resulting slurry wasstirred for 4 days under argon. The mixture was diluted with DCM. It wasfiltered through celite. The blue filtrate was washed with water (×2),dried, concentrated and purified by flash column to separately affordethyl 3-methyl-1-(6-methoxy-2-naphthyl)-1H-pyrazole-5-carboxylate [37%yield. Rf 0.80 (1:1 EtOAc:hexane). ES-MS: (M+H)⁺311] and ethyl5-methyl-1-(6-methoxy-2-naphthyl)-1H-pyrazole-3-carboxylate [25% yield.Rf 0.69 (1:1 EtOAc:hexane). ES-MS: (M+H)⁺311]in a 1.5:1 ratio.

[1123] Step 3. To a solution of2′-N-tert-butylaminosulfonyl-[1,1′]-biphenyl-4-ylamine (44 mg, 0.14mmol) in 1 mL DCM was added trimethylaluminum (2.0M in hexane, 0.35 mL,0.70 mmol) at room temperature. The mixture was stirred for 30 minutes,and to it was added the above-prepared ethyl3-methyl-1-(6-methoxy-2-naphthyl)-1H-pyrazole-5-carboxylate (44 mg, 0.14mmol) in 2 mL DCM. The resulting mixture was stirred overnight. Thereaction was quenched using 5 mL saturated Rochelle salt aq solution.The mixture was extracted using DCM (×3). The organic phases werecombined, dried, concentrated and subjected on flash column to affordthe coupling product in 84% yield (67 mg). Rf 0.41 (1:1 EtOAc:hexane).ES-MS: (M+H)⁺569.

[1124] Step 4. The above-prepared compound was placed in 3 mL TFA andstirred at 65 ±C for 30 minutes. After evaporation, the residue wasdissolved in methanol and purified with prep HPLC to afford the titlecompound in 95% yield. ES-MS: (M+H)⁺513.

Example 84

[1125]

[1126] Step 1. The preparation of ethyl3-methyl-1-(6-methoxy-2-naphthyl)-1H-pyrazole-5-carboxylate was the sameas described in Step 2 of Example 83.

[1127] Step 2. The above-prepared compound (150 mg, 0.48 mmol) wasdissolved in 2 mL DCM. At 0° C., to the stirred solution was added borontribromide (1.0M in DCM, 0.72 mL, 0.72 mmol). The mixture was stirredovernight at room temperature. It was directly subjected to flash columnto afford ethyl3-methyl-1-(6-hydroxy-2-naphthyl)-1H-pyrazole-5-carboxylate (78 mg,55%). Rf 0.73 (2:1 EtOAc:hexane). ES-MS: (M+H)⁺297.

[1128] Step 3. To a stirred solution of2′-N-tert-butylaminosulfonyl-[1,1′]-biphenyl-4-ylamine (80 mg, 0.26mmol) in 1 mL DCM was added trimethylaluminum (2.0M in hexane, 0.65 mL,1.3 mmol) at room temperature. After 30 minutes, to the mixture wasadded ethyl 3-methyl-1-(6-hydroxy-2-naphthyl)-1H-pyrazole-5-carboxylate(78 mg, 0.26 mmol) in 3 mL DCM. The resulting mixture was stirred 4hours. The reaction was quenched using 5 mL saturated Rochelle salt aqsolution. The mixture was extracted using DCM (×3). The organic phaseswere combined, dried, concentrated and purified with flash column toafford the coupling product in 65% yield. Rf 0.32 (1:1 EtOAc:hexane).ES-MS: (M+H)⁺555.

[1129] Step 4. The above-prepared compound was placed in 3 mL TFA andstirred at 70° C. for 30 minutes. After evaporation, the residue wasdissolved in methanol and purified with prep HPLC to afford the titlecompound in 95% yield. ES-MS: (M+H)⁺499.

Example 85

[1130]

[1131] Step 1. A mixture of 6-bromo-2-naphthoic acid (1.11 g, 4.4 mmol)and 2 mL thionyl chloride was refluxed for overnight. Thionyl chloridewas removed in vacuuo. The dry acid chloride was dissolved in 5 mLdioxane. At 0° C. to it was added a solution of sodium azide (0.52 g,8.0 mmol) in 2.5 mL water and 2.5 mL dioxane dropwise. The mixture wasstirred for 2 hours. After evaporation in vacuuo to remove the solvent,the residue was dissolved in EtOAc, washed with brine, dried,concentrated in vacuuo to give the azidoketone (1.22 g, 99%). Rf 0.88(1:1 EtOAc:hexane).

[1132] Step 2. The above-prepared compound was dissolved in 20 mL DMF.To it was added 10 mL water. The mixture was refluxed overnight. It wasdiluted with 500 mL EtOAc, washed with brine (×2), dried, concentratedin vacuuo to afford 6-bromo-2-naphthylamine (1.2 g, 99%). Rf 0.73 (1:1EtOAc:hexane), ES-MS: (M+H)⁺222, 224 (Br pattern).

[1133] Step 3. The above-prepared compound (1.2 g, 5.4 mmol) was placedin 6 mL concentrate HCl. At 0° C. to it was added a solution of sodiumnitrite (0.37 g, 5.4 mmol) in 2 mL water dropwise. The mixture wasstirred for 30 minutes. At 0° C. to the mixture was added a solution ofSnCl₂.2H₂O (3.66 g, 16.2 mmol) in 6 mL concentrate HCl dropwise. Afterstirring for 10 minutes, the mixture was placed in a freezer forovernight. The solid was collected on a cold Buchner funnel. It waswashed by ice-cold brine (7 mL) and ice-cold hexane (7 mL). The solidcake was transferred into a flask and pumped to dryness. To it wereadded 30 mL acetic acid, 15 mL THF, and ethyl2—N-(methoxy)imino-4-oxopentanoate (1.3 g, 7.0 mmol). The resultingmixture was refluxed for overnight. The solvent was removed in vacuuo.The residue was dissolved in EtOAc, washed with brine (×2), dried,concentrated and purified by flash column to yield ethyl3-methyl-1-(6-bromo-2-naphthyl)-1H-pyrazole-5-carboxylate (0.64 g, 33%).Rf0.71 (1:2 EtOAc:hexane). ES-MS: (+H)⁺359, 361 (Br pattern).

[1134] Step 4. To a stirred solution of2′-N-tert-butylaminosulfonyl-[1,1′]-biphenyl-4-ylamine (93 mg, 0.31mmol) in 1 mL DCM was added trimethylaluminum (2.0M in hexane, 0.70 mL,1.4 mmol) at room temperature. After 30 minutes, to the mixture wasadded the above-prepared ethyl ester (100 mg, 0.28 mmol) in 3 mL DCM.The resulting mixture was stirred overnight. The reaction was quenchedusing 5 mL saturated Rochelle's salt aq solution. The mixture wasextracted using DCM (×3). The organic phases were combined, dried,evaporated and purified with flash column to yield the coupling product(146 mg, 85%). Rf 0.44 (1:1 EtOAc:hexane). ES-MS: (M+H)⁺617, 619 (Brpattern).

[1135] Step 5. The above-prepared compound was placed in 3 mL TFA andstirred at 65° C. for 40 minutes. After evaporation, the residue wasdissolved in methanol and purified with prep KPLC to afford the titlecompound in 95% yield. ES-MS: (M+H)⁺561, 563 (Br pattern).

Example 86

[1136]

[1137] This compound was prepared by the same methodology described forExample 85 with2′-N-tert-butylaminosulfonyl-3-fluoro-[1,1′]-biphenyl-4-ylaminesubstituted for 2′-N-tert-butylaminosulfonyl-[1,1′]-biphenyl-4-ylamine.ES-MS: (M+H)⁺579, 581 (Br pattern).

Example 87

[1138]

[1139] This compound was prepared by the same methodology described forExample 85 with2′-N-tert-butylaminosulfonyl-3-chloro-[1,1′]-biphenyl-4-ylaminesubstituted for 2′-N-tert-butylaminosulfonyl-[1,1′]-biphenyl-4-ylamine.ES-MS: (M+H)⁺595, 597 (BrCl pattern).

Example 88

[1140]

[1141] This compound was prepared by the same methodology described forExample 85 with 2′-N-tert-butylaminosulfonyl-3-bromo-[1,1′]-biphenyl-4-ylamine substituted for2′-N-tert-butylaminosulfonyl-[1,1′]-biphenyl-4-ylamine. ES-MS:(M+H)⁺640, 642, 644 (Br₂ pattern).

Example 89

[1142]

[1143] This compound was prepared by the same methodology described forExample 85 with2′-N-tert-butylaminosulfonyl-5′-chloro-[1,1′]-biphenyl-4-ylaminesubstituted for 2′-N-tert-butylaminosulfonyl-[1,1′]-biphenyl-4-ylamine.ES-MS: (M+H) 595, 597 (BrCl pattern).

Example 90

[1144]

[1145] This compound was prepared by the same methodology described forExample 85 with 5-(2-N-tert-butylaminosulfonyl-1-phenyl)-2,3-dihydroindole substituted for2′-N-tert-butylaminosulfonyl-[1,1′]-biphenyl-4-ylamine. ES-MS:(M+H)⁺587, 589 (Br pattern).

Example 91

[1146]

[1147] Step 1. The synthesis of ethyl3-methyl-1-(6-bromo-2-naphthyl)-1H-pyrazole-5-carboxylate was the sameas Step 3 of Example 85.

[1148] Step 2. The above-prepared ethyl ester (1.0 g, 2.8 mmol) wasdissolved in 20 mL methanol. To the solution were added LiOH.H₂O (350mg, 8.3 mmol) and 10 mL water. The mixture was stirred for overnight andevaporated in vacuuo. The residue was acidified with 1N HCL. It wasextracted with EtOAc (×4). The organic phases were combined, dried andconcentrated in vacuuo to give3-methyl-1-(6-bromo-2-naphthyl)-1H-pyrazole-5-carboxylic acid (0.97 g,100%). ES-MS: (M+H)⁺331, 333 (Br pattern).

[1149] Step 3. A mixture of the above-prepared acid (33 mg, 0.10 mmol),2-amino-5-(2-(N-tert-butylaminosulfonyl)phenyl)pyridine (61 mg, 0.20mmol), DMAP (5 mg) were dissolved in 3 mL pyridine and stirred at 0° C.To it was added POCl₃ (55 μL, 0.6 mmol). The mixture was stirred for 2hours and quenched with ice chips. It was diluted with EtOAc, washedwith brine (×2), dried, concentrated and purified with flash column togive the coupling product (34 mg, 55%). Rf 0.35 (1:1 EtOAc:hexane).ES-MS: (M+H)⁺618, 620 (Br pattern).

[1150] Step 4. The above-prepared compound was placed in 3 mL TFA andstirred at 65° C. for 40 minutes. After evaporation, the residue wasdissolved in methanol and purified with prep HPLC to afford the titlecompound in 95% yield. ES-MS: (M+H)⁺562, 564 (Br pattern).

Example 92

[1151]

[1152] This compound was prepared by the same methodology described forExample 91 with2-amino-5-(2-(N-tert-butylaminosulfonyl)phenyl)pyrimidine substitutedfor 2-amino-5-(2-(N-tert-butylaminosulfonyl)phenyl)pyridine. ES-MS:(M+H)⁺563, 565 (Br pattern).

Example 93

[1153]

[1154] Step 1. The synthesis of3-methyl-1-(6-bromo-2-naphthyl)-1H-pyrazole-5-carboxylic acid was thesame as Step 2 of Example 91.

[1155] Step 2. A mixture of the above-prepared acid (970 mg, 2.9 mmol),4-aminobenzonitrile (700 mg, 5.8 mmol), DMAP (40 mg) were dissolved in15 mL pyridine and stirred at 0° C. To it was added POCl₃ (1.1 mL, 12mmol). The mixture was stirred for 1 hour and quenched with ice chips.It was diluted with EtOAc, washed with brine (×2), dried, concentratedand purified with flash column to give the coupling product (720 mg,58%). Rf 0.30 (1:1 EtOAc:hexane). ES-MS: (M+H)⁺431, 433 (Br pattern).

[1156] Step 3. The above-prepared nitrile (40 mg, 0.09 mmol) wasdissolved in 6 mL dry methanol. It was chilled and stirred in an icebath. To this solution was bubbled dry HCl gas via a long needle tillsaturation reached. The resulting solution was stirred overnight. ES-MS:(M+H)⁺463, 465 (Br pattern). The solvent was removed in vacuuo. Theresidue was pumped to dryness. The solid was dissolved in 6 mL drymethanol. To it was added anhydrous N-methylethylenediamine (0.5 mL).The mixture was refluxed for 1 hour, concentrated and loaded on prepHPLC to afford the title compound in 85% yield. ES-MS: (M+H)⁺488, 490(Br pattern).

Example 94

[1157]

[1158] This compound was prepared by the same methodology described forExample 93 with pyrrolidine substituted for N-methylethylenediamine.ES-MS: (M+H)⁺502, 504 (Br pattern).

Example 95

[1159]

[1160] This compound was prepared by the same methodology described forExample 93 with piperidine substituted for N-methylethylenediamine.ES-MS: (M+H)⁺516, 518 (Br pattern).

Example 96

[1161]

[1162] This compound was prepared by the same methodology described forExample 93 with morpholine substituted for N-methylethylenediamine.ES-MS: (M+H)⁺518, 520 (Br pattern).

Example 97

[1163]

[1164] This compound was prepared by the same methodology described forExample 93 with N-methylpiperazine substituted forN-methylethylenediamine. ES-MS: (M+H)⁺531, 533 (Br pattern).

Example 98

[1165]

[1166] This compound was prepared by the same methodology described forExample 93 with 4-amino-3-fluorobenzonitrile substituted for4-aminobenzonitrile. ES-MS: (M+H)⁺506, 508 (Br pattern).

Example 99

[1167]

[1168] This compound was prepared by the same methodology described forExample 93 with 4-amino-2,5-difluorobenzonitrile substituted for4-aminobenzonitrile. ES-MS: (M+H)⁺524, 526 (Br pattern).

Example 100

[1169]

[1170] This compound was prepared by the same methodology described forExample 93 with 4-amino-3-chlorobenzonitrile substituted for4-aminobenzonitrile. ES-MS: (M+H)⁺522, 524 (BrCl pattern).

Example 101

[1171]

[1172] This compound was prepared by the same methodology described forExample 93 with 4-amino -2-chloroberzonitrile substituted for4-aminobenzonitrile. ES-MS: (M+H)⁺522, 524 (BrCl pattern).

Example 102

[1173]

[1174] This compound was prepared by the same methodology described forExample 93 with 4-amino-2-chlorobenzonitrile substituted for4-aminobenzonitrile, and with N-ethyl ethylenediamine substituted forN-methylethylenediamine. ES-MS: (M+H)⁺536, 538 (BrCl pattern).

Example 103

[1175]

[1176] This compound was prepared by the same methodology described forExample 93 with 4-amino-3-chlorobenzonitrile substituted for4-aminobenzonitrile, and with ethylenediamine substituted forN-methylethylenediamine. ES-MS: (M+H)⁺508, 510 5 (BrCl pattern).

Example 104

[1177]

[1178] This compound was prepared by the same methodology described forExample 93 with 4-amino-3-chlorobenzonitrile substituted for4-aminobenzonitrile, and with N-methyl-1,3-propanediamine substitutedfor N-methylethylenediamine. ES-MS: (M+H)⁺536, 538 (BrCl pattern).

Example 105

[1179]

[1180] This compound was prepared by the same methodology described forExample 93 with 4-amino-3-chlorobenzonitrile substituted for4-aminobenzonitrile, and with 1,3-propanediamine substituted forN-methylethylenediamine. ES-MS: (M+H)⁺522, 524 (BrCl pattern).

Example 106

[1181]

[1182] This compound was prepared by the same methodology described forExample 93 with 4-amino-3-fluorobenzonitrile substituted for4-aminobenzonitrile, and with pyrrolidine substituted forN-methylethylenediamine. ES-MS: (M+H)⁺520, 522 (Br pattern).

Example 107

[1183]

[1184] This compound was prepared by the same methodology described forExample 93 with 4-amino-3-fluorobenzonitrile substituted for4-aminobenzonitrile, and with 2-methylpyrrolidine substituted forN-methylethylenediamine. ES-MS: (M+H )⁺534, 536 (Br pattern).

Example 108

[1185]

[1186] This compound was prepared by the same methodology described forExample 93 with 4-amino-2,5-difluorobenzonitrile substituted for4-aminobenzonitrile, and with pyrrolidine substituted forN-methylethylenediamine. ES-MS: (M+H)⁺538, 540 (Br pattern).

Example 109

[1187]

[1188] This compound was prepared by the same methodology described forExample 93 with 4-amino-3-chlorobenzonitrile substituted for4-aminobenzonitrile, and with pyrrolidine substituted forN-methylethylenediamine. ES-MS: (M+H)⁺536, 538 (BrCl pattern).

Example 110

[1189]

[1190] This compound was prepared by the same methodology described forExample 93 with 4-amino-2-chlorobenzonitrile substituted for4-aminobenzonitrile, and with pyrrolidine substituted forN-methylethylenediamine. ES-MS: (M+H)⁺536, 538 (BrCl pattern).

Example 111

[1191]

[1192] This compound was prepared by the same methodology described forExample 93 with 4-amino-3-fluorobenzonitrile substituted for4-aminobenzonitrile, and with thiomorpholine substituted for N-methylethyl enediamine. ES-MS: (M+H)⁺552, 554 (Br pattern).

Example 112

[1193]

[1194] This compound was prepared by the same methodology described forExample 93 with 4-amino-3-fluorobenzonitrile substituted for4-aminobenzonitrile, and with ammonium acetate substituted forN-methylethylenediamine. ES-MS: (M+H)⁺466, 468 (Br pattern).

Example 113

[1195]

[1196] This compound was prepared by the same methodology described forExample 93 with 4-amino -2,5-difluorobenzonitrile substituted for4-aminobenzonitrile, and with methyl amine (2M in methanol) substitutedfor N-methyl ethylenediamine. ES-MS: (M+H)⁺498, 500 (Br pattern).

Example 114

[1197]

[1198] This compound was prepared by the same methodology described forExample 93 with 4-amino-3-chlorobenzonitrile substituted for4-aminobenzonitrile, and with dimethylamine (2M in THF) substituted forN-methylethylenediamine. ES-MS: (M+H)⁺510, 512 (BrCl pattern).

Example 115

[1199]

[1200] Step 1. To a solution of 6-bromo-2-naphthoic acid (4.4 g, 17.5mmol) in 50 mL anhydrous DMF were added CuCl (8.7 g, 87.5 mmol) and CuI(0.2 g). The slurry was refluxed for 1 hour. At room temperature it wasdiluted with 300 mL EtOAc and stirred for 2 hours. It was filteredthrough celite. The filtrate was evaporated in vacuuo to afford6-chloro-2-naphthoic acid (2.7 g, 75%). ES-MS: (M+H)⁺207.

[1201] Step 2. The title compound was prepared using the samemethodology shown for Example 85, with 6-chloro-2-naphthoic acidsubstituted for 6-bromo-2-naphthoic acid. ES-MS: (M+H)⁺517.

Example 116

[1202]

[1203] The title compound was prepared using the same methodology shownfor Example 115, with2′-N-tert-butylaminosulfonyl-3-fluoro-[1,1′]-biphenyl-4-ylaminesubstituted for 2′-N-tert-butylaminosulfonyl-[1,1 ′]-biphenyl-4-ylamine.ES-MS: (M+H)⁺535.

Example 117

[1204]

[1205] The title compound was prepared using the same methodology shownfor Example 115, with 2′-methylsulfonyl-3-fluoro-[1,1′]biphenyl-4-ylamine substituted for2′-N-tert-butylaminosulfonyl-[1,1′]-biphenyl-4-yl amine. ES-MS:(M+H)⁺534.

Example 118

[1206]

[1207] The title compound was prepared using the same methodology shownfor Example 98, with 6-chloro-2-naphthoic acid substituted for6-bromo-2-naphthoic acid. ES-MS: (M+H)⁺462.

Example 119

[1208]

[1209] The title compound was prepared using the same methodology shownfor Example 106, with 6-chloro-2-naphthoic acid substituted for6-bromo-2-naphthoic acid. ES-MS: (M+H)⁺476.

Example 120

[1210]

[1211] The title compound was prepared using the same methodology shownfor Example 119, with piperidine substituted forN-methylethylenediamine. ES-MS: (M+H)⁺490.

Example 121

[1212]

[1213] The title compound was prepared using the same methodology shownfor Example 119, with dimethylamine (2M in THF) substituted forN-methylethylenediamine. ES-MS: (M+H)⁺450.

Example 122

[1214]

[1215] Step 1. The synthesis of3-methyl-1-(3-cyano-2-naphthyl)-1H-pyrazole-5-(N-(2′-N-tert-butylaminosulfonyl-[1,1′]-biphen-4-yl))carboxyamidefollowed the same procedure shown in Step 3 of Example 34.

[1216] Step 2. To a solution of the above-prepared compound (30 mg) in10 mL anhydrous ethanol at 0° C. was bubbled dry HCl gas via a longneedle till saturation reached. The mixture was stirred for overnight.The solvent was removed in vacuuo. The dry residue was dissolved in 5 mLanhydrous methanol. To it was added 0.5 mL N-methylethylenediamine. Themixture was refluxed for 2 hours. ES-MS: (M+H)⁺621. It was concentratedin vacuuo. To the residue was added 3 mL TFA and the mixture was stirredat 70° C. for 1 hour. After evaporation, the reaction mixture wassubjected on prep BPLC to isolate the title compound (20% yield). ES-MS:(M+H)⁺565.

Example 123

[1217]

[1218] The title compound was prepared using the same methodology shownfor Example 122, with dimethylamine (2M in TMF) substituted forN-methylethylenediamine. ES-MS: (M+H)⁺553.

Example 124

[1219]

[1220] The title compound was prepared using the same methodology shownfor Example 122, with pyrrolidine substituted forN-methylethylenediamine. ES-MS: (M+H)⁺579.

Example 125

[1221]

[1222] The title compound was prepared using the same methodology shownfor Example 1, with 2—N-tert-butylaniinosulfonylphenylboronic acidsubstituted for 2-naphthylboronic acid. ES-MS: (M+H)⁺512.

Example 126

[1223]

[1224] The title compound was prepared using the same methodology shownfor Example 1, with 2-methylsulfonylphenylboronic acid substituted for2-naphthylboronic acid. ES-MS: (M+H)⁺511.

Example 127

[1225]

[1226] The title compound was prepared using the same methodology shownfor Example 52, with commercial 2-nitrophenylhydrazine substituted for3-carboxyl-2-naphthylhydrazine. ES-MS: (M+H)⁺478.

Example 128

[1227]

[1228] Step 1. 4-methylsulfonyl-3-nitrobenzoic acid (0.90 g, 3.7 mmol)was dissolved in 10 mL ethanol. To it were added hydrazine monohydrate(0.46 mL, 15 mmol) and catalytic amount of 10% Pd/C. The mixture wasrefluxed for 1.5 hour, diluted with methanol, filtered through celiteand concentrated in vacuuo to afford 3-amino-4-methylsulfonylbenzoicacid (>70%). ES-MS: (M+H)⁺216.

[1229] Step 2. The above-prepared aniline (2.2 g, 10 mmol) was stirredin 16 mL concentrate HCl in ice bath. To it was dropwise added a coldsolution of sodium nitrite (1.1 g, 15 mmol, in 7 mL water). Aftercompletion, the mixture was stirred for 30 minutes at 0° C. To it wasadded dropwise a cold solution of SnCl₂.2H₂O (9.2 g, 40 mmol, in 14 mLconcentrate HCl). The mixture was stirred for 30 minutes and filteredthrough a Buchner funnel. The solid crude hydrazine was collected anddried.

[1230] Step 3. The crude hydrazine was dissolved in 40 mL acetic acid.To it were added 20 mL THF and ethyl 2-N-(methoxy)imino-4-oxopentanoate(2.8 g, 15 mmol). The mixture was refluxed for overnight. After removalof the solvent in vacuuo, the reaction mixture residue was dissolved in800 mL ether. The organic solution was washed with brine (×2), dried,concentrated and purified with flash column to afford ethyl3-methyl-1-(5-carboxyl-2-methylsulfonylphenyl)-1H-pyrazole-5-carboxylate(2.1 g, 60%). Rf 0.17 (pure EtOAc). ES-MS: (M+H)⁺353.

[1231] Step 4. The above-prepared acid (2.1 g, 6.5 mmol) was dissolvedin 50 mL dry DMF. To it were added tert-butylamine (1.4 mL, 13 mmol),DIEA (9.2 mL, 52 mmol) and PyBOP (13 g, 26 mmol) in order. The resultingmixture was stirred for overnight at room temperature. DMF was removedin vacuuo. The residue was taken into EtOAc and washed with brine (×2).The organic phase was dried, concentrated and subjected on flash columnto isolate ethyl3-methyl-1-(5-N-tert-butylaminocarbonyl-2-methylsulfonylphenyl)-1H-pyrazole-5-carboxylate(0.74 g, 30%). Rf 0.70 (pure EtOAc). ES-MS: (M+H)⁺408.

[1232] Step 5. To a solution of2′-N-tert-butylaminosulfonyl-[1,1′]-biphenyl-4-ylamine (100 mg, 0.33mmol) in 2 mL DCM was added trimethylaluminum (2.0M in hexane, 0.66 mL,1.3 mmol) under argon at room temperature. After being stirred for 30minutes, to the mixture was added the above-prepared ester (90 mg, 0.22mmol) in 10 mL DCM. The resulting mixture was stirred overnight. Thereaction was quenched using 10 mL saturated Rochelle's salt aq solution.The mixture was extracted using DCM (×3). The organic phases werecombined, dried, rotovaped and subjected on flash chromatography columnto give the coupled product in 62% yield (90 mg). Rf 0.10 (1:1EtOAc:hexane). ES-MS: (M+H)⁺666.

[1233] Step 6. The above-prepared compound (20 mg) was placed in 5 mLTFA. It was stirred at 70° C. for 1 hour and subjected on prep HPLC toisolate the title compound (90%) after evaporation. ES-MS: (M+H)⁺554.

Example 129

[1234]

[1235] Step 1. To a solution of 4-biphenylboronic acid (1.0 g, 5.1 mmol)and ethyl 3-methylpyrazole-5-carboxylate (0.78 g, 5.1 mmol) in 25 mL dryDCM were added pyridine (1.2 mL, 15 mmol) and anhydrous powder ofcopper(II) acetate (1.84 g, 10 mmol). Some activated molecular sievepowder was added afterwards. The resulting slurry was refluxed for 2days under argon. The mixture was diluted with DCM, filtered throughcelite. The blue filtrate was washed with water (×2), dried,concentrated, purified with flush column to yield ethyl3-methyl-1-(4-phenylphenyl)-1H-pyrazole-5-carboxylate (26%), Rf 0.67(1:2 EtOAc:hexane), ES-MS: (M+H)⁺307; and its regioisomer, ethyl5-methyl-1-(4-phenylphenyl)-1H-pyrazole-3-carboxylate (31%), Rf 0.50(1:2 EtOAc:hexane), ES-MS: (M+H)⁺307.

[1236] Step 2. To a stirred solution of 4-chloroaniline (24 mg, 0.18mmol) in 1 mL DCM was added trimethylaluminum (2.0M, 0.43 mL, 0.86 mmol)at room temperature. After 30 minutes, to the mixture was added ethyl3-methyl-1-(4-phenylphenyl)-1H-pyrazole-5-carboxylate (52 mg, 0.17 mmol)in 3 mL DCM. The resulting mixture was stirred for overnight. It wasquenched using 5 mL saturated Rochelle's salt aq solution. The mixturewas extracted using DCM (×3). The organic phases were combined, dried,concentrated and subjected on flash column to afford the title compound(46 mg, 70%). Rf 0.46 (1:1 EtOAc:hexane). ES-MS: (M+H)⁺388.

Example 130

[1237]

[1238] The title compound was prepared using the same methodology shownfor Example 129, with 4-methoxyaniline substituted for 4-chloroaniline.ES-MS: (M+H)⁺384.

Example 131

[1239]

[1240] Step 1. 2′-N-tert-butylaminosulfonyl-[1,1′]-biphenyl-4-ylamine(1.9 g, 6.2 mmol) was placed in 8 mL concentrate HCl. At 0° C. to thisstirred mixture was added a cold solution of sodium nitrite (0.43 g, 6.2mmol in 2 mL water) dropwise. After 30 minutes, to it was added a coldsolution of SnCl₂.2H₂O (4.2 g, 18.4 mmol in 8 mL concentrate HCl). Themixture was stirred at 0° C. for 1 hour and the solid was collected witha Buchner funnel. The crude solid hydrazine was dried.

[1241] Step 2. The above-prepared crude hydrazine was dissolved in 20 mLacetic acid. To it was added 10 mL TMF and ethyl2-N-(methoxy)imino-4-oxopentanoate (0.93 g, 5.0 mmol). The mixture wasrefluxed for 3 hours. The solvent was removed in vacuuo. The residue wastaken into EtOAc, washed with brine, dried, concentrated and purifiedwith flash column to yield ethyl3-methyl-1-(4-(2-aminosulfonylphenyl)-phenyl)-1H-pyrazole-5-carboxylate(0.95 g, 40%). Rf 0.51 (1:1 EtOAc:hexane). ES-MS: (M+H)⁺386.

[1242] Step 3. The above-prepared ethyl ester was dissolved in 20 mLmethanol. To it were added LiOH.H₂O (0.31 g, 7.4 mol) and 10 mL water.The mixture was stirred for 3 hours, acidifed till pH 5 with aceticacid, and evaporated in vacuuo. The residue was soaked with acetonitrileand decanted for several times to extract out the organic product. Theacetonitrile solutions were combined and evaporated in vacuuo to giveyield3-methyl-1-(4-(2-aminosulfonylphenyl)-phenyl)-1H-pyrazole-5-carboxylicacid (0.81 g, 92%). ES-MS: (M+H)⁺358. It was further purified using prepHPLC.

[1243] Step 4. The above-prepared acid (20 mg, 0.056 mmol) was dissolvedin 1 mL dry DMF. To it were added 4-bromoaniline (10 mg, 0.056 mmol),DIEA (30 μL, 0.17 mmol) and PyBOP (58 mg, 0.12 mmol) in order. Thereaction mixture was directly loaded on prep KPLC to yield the titlecompound in 45% yield. ES-MS: (M+H)⁺511, 513 (Br pattern).

Example 132

[1244]

[1245] The title compound was prepared using the same methodology shownfor Example 131, with 4-methoxyaniline substituted for 4-bromoanihine.ES-MS (M+H)⁺463.

Example 133

[1246]

[1247] The title compound was prepared using the same methodology shownfor Example 131, with 4-methoxy-2-nitroaniline substituted for4-bromoaniline . ES-MS: (M+H)⁺508.

Example 134

[1248]

[1249] The title compound was prepared using the same methodology shownfor Example 131, with 6-bromo-2-naphthylamine substituted for4-bromoaniline. ES-MS: (M+H)⁺562, 564 (Br pattern).

Example 135

[1250]

[1251] The title compound was prepared using the same methodology shownfor Example 131, with 2-naphthylamine substituted for 4-bromoaniline.ES-MS: (M+H)⁺483.

Example 136

[1252]

[1253] The title compound was prepared using the same methodology shownfor Example 131, with 7-aminoisoquinoline substituted for4-bromoaniline. ES-MS: (M+H)⁺484.

Example 137

[1254]

[1255] The title compound was prepared using the same methodoogy shownfor Example 131, with 2-amino-5-chloropyridine substituted for4-bromoaniline. ES-MS: (M+H)⁺468.

Example 138

[1256]

[1257] The title compound was prepared using the same methodology shownfor Example 131, with 2-amino-5-bromopyridine substituted for4-bromoaniline. ES-MS: (M+H)⁺512, 154 (Br pattern).

Example 139

[1258]

[1259] Step 1. A mixture of 4-cyanophenylhydrazine hydrochlorde (5.7 g,33 mmol), ethyl 2-N-(methoxy)imino-4-oxopentanoate (7.5 g, 40 mmol), 100mL acetic acid and 50 mL THF was refluxed for 2 hours. The solvent wasremoved in vacuuo. The residue was taken into 500 mL EtOAc, which waswashed with brine, dried and evaporated in vacuuo to afford ethyl3-methyl-1-(4-cyanophenyl)-1H-pyrazole-5-carboxylate (10 g, 99%). ES-MS:(M+H)⁺256.

[1260] Step 2. The above-prepared ester (10 g) was dissolved in 100 mnLTHF. To it were added LiOH.H₂O (4.2 g, 100 mmol), 100 mL methanol and 50mL water. The mixture was stirred for 1 hour. It was acidified to pH 1with 1N HCl. It was evaporated to remove organic solvent. The residuewas extracted with EtOAc (×4). The organic phases were combined, driedand evaporated to dryness to afford3-methyl-1-(4-cyanophenyl)-1H-pyrazole-5-carboxylatic acid (95%). ES-MS:(M+H)⁺228.

[1261] Step 3. The above-prepared acid (1.4 g, 6.2 mmol) was dissolvedin 20 mL pyridine. To it were added 2-amino-5-bromopyridine (2.2 g, 13mmol) and DMAP (100 mg). At 0° C. to this mixture was added POCl₃ (2.3mL, 25 mmol). The reaction was allowed for 1.5 hour and quenched withice chips. After evaporation in vacuuo, the residue was taken into 300mL EtOAc, which was washed with brine, dried, evaporated and purifiedwith flash column to yield the coupling product (45%). Rf 0.52 (1:1EtOAc:hexane). ES-MS: (M+H)⁺382, 384 (Br pattern).

[1262] Step 4. To a solution of the above-prepared nitrile (30 mg) in 10mL anhydrous methanol at 0° C. was bubbled dry HCl gas via a long needletill saturation reached. The mixture was stirred for overnight. Thesolvent was removed in vacuuo. The dry residue was dissolved in 5 mLanhydrous methanol. To it was added 0.5 mL N-methylethylenediamine. Themixture was refluxed for 1 hour. After evaporation, the reaction mixturewas subjected on prep HPLC to isolate the title compound (80% yield).ES-MS: (M+H)⁺439, 441 (Br pattern).

Example 140

[1263]

[1264] The title compound was prepared using the same methodology shownfor Example 139, with ethylenediamine substituted forN-methylethylenediamine. ES-MS: (M+H)⁺425, 427 (Br pattern).

Example 141

[1265]

[1266] The title compound was prepared using the same methodology shownfor Example 139, with pyrrolidine substituted forN-methylethylenediamine. ES-MS: (M+H)⁺453, 455 (Br pattern).

Example 142

[1267]

[1268] The title compound was prepared using the same methodology shownfor Example 139, with 2-methylpyrrolidine substituted forN-methyletliylenediamine. ES-MS: (M+H)⁺467, 469 (Br pattern).

Example 143

[1269]

[1270] The title compound was prepared using the same methodology shownfor Example 139, with piperidine substituted forN-methylethylenediamine. ES-MS: (M+H)⁺467, 469 (Br pattern).

Example 144

[1271]

[1272] The title compound was prepared using the same methodology shownfor Example 139, with morpholine substituted forN-methylethylenediamine. ES-MS: (M+H)⁺469, 471 (Br pattern).

Example 145

[1273]

[1274] The title compound was prepared using the same methodology shownfor Example 139, with thiomorpholine substituted forN-methylethylenediamine. ES-MS: (M+H)⁺485, 487 (Br pattern).

Example 146

[1275]

[1276] The title compound was prepared using the same methodology shownfor Example 139, with N-metliylpiperazine substituted forN-methylethylenediamine. ES-MS: (M+H) +482, 484 (Br pattern).

Example 147

[1277]

[1278] The title compound was prepared using the same methodology shownfor Example 139, with hexamethyleneimine substituted forN-methylethylenediamine. ES-MS: (M+H)⁺481, 483 (Br pattern).

Example 148

[1279]

[1280] The title compound was prepared using the same methodology shownfor Example 139, with 1-methyihomopiperazine substituted for N-methylethylenedi amine. ES-MS: (M+H)⁺496, 498 (Br pattern).

Example 149

[1281]

[1282] The title compound was prepared using the same methodology shownfor Example 139, with dimethylamine (2M in TMF) substituted forN-methylethylenediamine. ES-MS: (M+H)⁺427, 429 (Br pattern).

Example 150

[1283]

[1284] The title compound was prepared using the same methodology shownfor Example 139, with ammonium acetate substituted forN-methylethylenediamine. ES-MS: (M+H)⁺399, 401 (Br pattern).

Example 151

[1285]

[1286] The preparation of3-methyl-1-(3-fluoro-2-naphthyl)-1H-pyrazole-5-carboxylic acid was thesame as that in Step 1 for Example 4. This acid (39 mg, 0.12 mmol) and4-isopropoxyaniline (36 mg, 0.24 mmol) were dissolved in 1.4 mLpyridine. To it was added catalytic amount of DMAP. In ice bath, to thisstirred mixture was added POCl₃ (45 μL, 0.48 mmol). The reaction wasallowed for 1 hr and quenched with ice chips. The reaction mixture wasdiluted with EtOAc. It was washed with brine, dried, evaporated andpurified with flash column. Yield 24 mg (50%). Rf 0.53 (1:1EtOAc:hexane). ES-MS: (M+H)⁺404.

Example 152

[1287]

[1288] The title compound was prepared by the same technology describedfor Example 4 with 2′-methylsulfonyl-[1,1 ′]-biphenyl-4-ylaminesubstituted2′-N-tert-butylaminosulfonyl-3-fluoro-[1,1′]-biphenyl-4-ylamine, withoutthe TFA treatment followed. ES-MS: (M+H)⁺500.

Example 153

[1289]

[1290] The title compound was prepared by the same technology describedfor Example 4 with 2′-methylsulfonyl-3-fluoro-[1,1 ′]-biphenyl-4-ylaminesubstituted2′-N-tert-butylaminosulfonyl-3-fluoro-[1,1′]-biphenyl-4-ylamine, withoutthe TFA treatment followed. ES-MS: (M+H)⁺518.

Example 154

[1291]

[1292] Step 1. The mixture of 1 -fluoro-4-nitrobenzene (880 mg, 6.2mmol), 1-methylhomopiperazine (2.3 mL, 18.6 mmol), Cs₂CO₃ (6.1 g, 18.6mmol) in 20 mL DMF was stirred at 100° C. for 1.5 hr. It was dilutedwith DCM, filtered to remove the inorganic salts, washed with water,dried, evaporated in vacuuo to afford1-(4-nitrophenyl)-4-methylhomopiperazine in quantitative yield. ES-MS:(M+H)⁺236.

[1293] Step 2. The nitro compound (300 mg) made above was dissolved in10 mL ethanol. To it was added 10% Pd/C of catalytic amount. The blackslurry was stirred under a hydrogen balloon for overnight. The mixturewas diluted with EtOAc, filtered through celite, evaporated in vacuuo toafford 1-(4-aminophenyl)-4-methylhomopiperazine in quantitative yield.ES-MS: (M+H)⁺206.

[1294] Step 3. 3-Methyl-1-(3-fluoro-2-naphthyl)-1H-pyrazole-5-carboxylicacid (see Step 1, Example 4) (81 mg, 0.3 mmol) and1-(4-aminophenyl)-4-methylhomopiperazine (205 mg, 1 mmol) were dissolvedin 3 mL pyridine. In 0° C. to this stirred mixture was added POCl₃ (0.18mL, 2 mmol). The reaction was allowed for 2 hrs and quenched with 1 mLmethanol. The mixture was purified using a short silica plug. The crudeproduct was further purified using KPLC. ES-MS: (M+H)⁺458.

Example 155

[1295]

[1296] Step 1. 1-Boc-4-(4-nitrophenyl)homopiperazine (prepared with1-fluoro-4-nitrobenzene, 1-Boc-homopiperazine, Cs₂CO₃ in heated DMF) wasdissolved in methanol. To it was added 10% Pd/C. The slurry was stirredunder a hydrogen balloon for 2 hrs. It was filtered through celite andevaporated in vacuuo to give 1-(4-aminophenyl)-4-Boc-homopiperazine.ES-MS: (M+H)⁺292.

[1297] Step 2. 3-Methyl-1-(3-fluoro-2-naphthyl)-1H-pyrazole-5-carboxylicacid (see Step 1, Example 4) (54 mg, 0.2 mmol) and1-(4-aminophenyl)-4-Boc-homopiperazine (116 mg, 0.4 mmol) were dissolvedin 3 mL pyridine. In 0° C. to this stirred mixture was added POCl₃ (0.08mL, 0.8 mmol). The reaction was allowed for 1.5 hrs and quenched withwater. The mixture was diluted with EtOAc, washed with water, dried,concentrated in vacuuo to give the coupling amide product. ES-MS:(M+H)⁺544. It was dissolved in 20 mL methanol and to it was bubbled HClgas till saturation. The mixture was stirred for overnight. It wasevaporated in vacuuo to afford3-methyl-1-(3-fluoro-2-naphthyl)-1H-pyrazole-5-[4-(1-homopiperazinyl)phenyl]carboxyamide.ES-MS: (M+H)⁺444.

[1298] Step 3. The above compound (30 mg, 0.07 mmol) was dissolved in 5mL dry methanol. To it were added ethyl acetimidate HCl (42 mg, 0.35mmol) and DIEA (0.06 mL, 0.35 mmol). The mixture was refluxed forovernight and subjected to prep HPLC to afford the title compound.ES-MS: (M+H)⁺485.

Example 156

[1299]

[1300] To the mixture of3-methyl-1-(3-fluoro-2-naphthyl)-1H-pyrazole-5-[4-(1-homopiperazinyl)phenyl]carboxyamide(30 mg, 0.07 mmol) in 2 mL pyridine and 2 mL DCM was added acetylchloride (0.05 mL, 0.7 mmol). The reaction was allowed for 1 hr. Thetitle compound was afforded after prep HPLC purification in quantitativeyield. ES-MS: (M+H)⁺486.

Example 157

[1301]

[1302] The title compound was prepared using the same methodologydescribed for Example 155, with 1-Boc-piperazine substituted for1-Boc-homopiperazine. ES-MS: (M+H)⁺471.

Example 158

[1303]

[1304] The title compound was prepared using the same methodologydescribed for Example 156, with 1-Boc-piperazine substituted for1-Boc-homopiperazine. ES-MS: (M+H)⁺472.

Example 159

[1305]

[1306] Step 1. The mixture of 4-pyridineboronic acid (0.97 g, 7.8 mmol),4-Boc-aminopiperidine (3.25 g, 15.8 mmol), Cu(OAc)₂ (2.88 g, 15.8 mmol),DMAP (catalytic amount), pyridine (2.5 mL, 32 mmol), 4A activatedmolecular sieve in 50 mL dry DCM was stirred for over 2 days. It wasdiluted with DCM, filtered through celite. It was washed with brine andwater, dried, filtered through a silica plug, evaporated in vacuuo togive 4-(4-Boc-aminopiperidin-1-yl)pyridine in 90% yield. ES-MS: (+H)278.

[1307] Step 2. The above-prepared compound was dissolved in 50 mLmethanol. To it was bubbled HCl gas till saturation in an ice bath. Thereaction mixture was stirred for 3 hrs. Evaporated in vacuuo to yield(4-aminopiperidin-1-yl)pyridine. ES-MS: (M+H)⁺178.

[1308] Step 3. 3-Methyl-1-(3-fluoro-2-naphthyl)-1H-pyrazole-5-carboxylicacid (see Step 1, Example 4) (48 mg, 0.2 mmol) and4-(4-aminopiperidin-1-yl)pyridine (95 mg, 0.5 mmol) were dissolved in1.4 mL pyridine. In 0° C. to this stirred mixture was added POCl₃ (0.1mL, 1 mmol). The reaction was allowed for 1 hr and quenched withmethanol. The mixture was subjected to prep HPLC to isolate the titlecompound. ES-MS: (M+H)⁺430.

Example 160

[1309]

[1310] Step 1. 3-Methyl-1-(3-fluoro-2-naphthyl)-1H-pyrazole-5-carboxylicacid (see Step 1, Example 4) (316 mg, 1.2 mmol) and1-N-Boc-4-aminopiperidine (480 mg, 2.4 mmol) were dissolved in 10 mLpyridine. In 0° C. to this stirred mixture was added POCl₃ (0.45 mL 4.8mmol). The reaction was allowed for 1 hr and quenched with methanol. Themixture was subjected to flash column to isolate the amide in 65% yield(350 mg). Rf 0.10 (1:2EtOAc:hexane). ES-MS: (M+H)⁺453.

[1311] Step 2. The above compound was dissolved in 20 mL dioxane. To itwas bubbled HCl gas till saturation. The mixture was stirred forovernight. It was evaporated in vacuuo to yield3-methyl-1-(3-fluoro-2-naphthyl)-1H-pyrazole-5-(4-piperidinyl)carboxyamide.ES-MS: (M+H)⁺353.

[1312] Step 3. The above compound (52 mg, 0.15 mmol) was dissolved in 4mL methanol. To it were added acetic acid (0.2 mL), acetone (0.22 mL, 3mmol), NaBH₃CN (38 mg, 0.6 mmol). The mixture was stirred in 50° C. bathfor 5 hrs. The title compound was isolated with prep HPLC in 80% yield.ES-MS: (M+H)⁺395.

Example 161

[1313]

[1314] The title compound was prepared using the same methodology shownfor Example 160, with cyclopentanone substituted for acetone. ES-MS:(M+H)⁺421.

Example 162

[1315]

[1316] The title compound was prepared using the same methodologydescribed for Example 22, with dimethylanune substituted forN-methylethylenediamine. ES-MS: (M+H)⁺434.

Example 163

[1317]

[1318] The title compound was prepared using the same methodologydescribed for Example 28, with dimethylamine substituted forN-methylethylenediamine. ES-MS: (M+H)⁺452.

Example 164

[1319]

[1320] The title compound was prepared using the same methodologydescribed for Example 163, with 4-amino-3-chlorobenzonitrile substitutedfor 4-amino-2,5-diflourobenzonitrile. ES-MS: (M+H)⁺450.

Example 165

[1321]

[1322] The title compound was prepared using the same methodologydescribed for Example 163, with 4-amino-2-chlorobenzonitrile substitutedfor 4-amino-2,5-diflourobenzonitrile. ES-MS: (M+H)⁺450.

Example 166

[1323]

[1324] Step 1. 3-Methyl-1-(3-fluoro-2-naphthyl)-1H-pyrazole-5-carboxylicacid (see Step 1, Example 4) (828 mg, 3.1 mmol) was dissolved in 20 mLdry DCM. To it were added 0.05 mL DMF and oxalyl chloride (0.81 mL, 9.3mL). The mixture was stirred for 2 hrs. It was evaporated in vacuuo. Theresidue was dissolved in 30 mL dry dioxane. It was chilled in ice bath.To the stirred cold mixture was added dropwise a chilled solution ofsodium azide (0.4 g, 6.2 mmol) in 2 mL water and 1 mL dioxane. Reactionwas allowed for 1 hr. It was evaporated in vacuuo. The residue was takeninto EtOAc and washed with water ×2. The organic phase was dried andconcentrated in vacuuo. The organic residue was then dissolved in 30 mLDMF. To it was added 15 mL water. The mixture was refluxed for 2.5 hrs.It was concentrated in vacuuo and purified using flash column to give3-methyl-1-(3-fluoro-2-naphthyl)-5-amino-1H-pyrazole (280 mg, 38%overall). Rf 0.45 (1:1 EtOAc:hexane). ES-MS: (M+H)⁺242.

[1325] Step 2. The mixture of above amine (200 mg, 0.83 mmol) and4-cyanobenzoyl chloride (205 mg, 1.2 mmol) in pyridine (10 mL) withcatalytic amount of DMAP was stirred for overnight. The reaction mixturewas evaporated in vacuuo and loaded on flash column to give the isolatedamide product (50% yield).). Rf 0.45 (1:1 EtOAc:hexane). ES-MS:(M+H)⁺371.

[1326] Step 3. The above-prepared nitrile (30 mg, 0.08 mmol) wasdissolved in 10 mL dry methanol. It was chilled and stirred in an icebath. To this solution was bubbled dry HCl gas via a long needle tillsaturation reached (indicated by a blown-up balloon attached on the topof the reaction flask). The resulting solution was stirred overnight.ES-MS: (M+H)⁺403. The solvent was removed in vacuuo. The residue waspumped to dryness. The solid was dissolved in 5 mL dry methanol. To itwas added dimethylamine (2M in THF, 0.5 mL). The mixture was refluxedfor 1 hour, concentrated and loaded on prep HPLC to afford the titlecompound in 60% yield. ES-MS: (M+H)⁺416.

Example 167

[1327]

[1328] The title compound was prepared using the same methodologydescribed for Example 166, with pyrrolidine substituted fordimethylamine. ES-MS: (M+H)⁺442.

Example 168

[1329]

[1330] The title compound was prepared using the same methodologydescribed for Example 166, with piperdine substituted for dimethylamine.ES-MS: (M+H)⁺456.

Example 169

[1331]

[1332] The title compound was prepared using the same methodologydescribed for Example 166, with N-methylethylenediamine substituted fordimethylamine. ES-MS: (M+H)⁺428.

Example 170

[1333]

[1334] Step 1. 3-fluoro-2-naphthylamine (1.38 g, 8.57 mmol, see Step 2,Example 3) was placed in 20 mL concentrate HCl. The slurry was stirredin ice bath. To it was added dropwise a chilled solution of sodiumnitrite (0.71 g, 10.3 mmol) in 4 mL water. After completion, the mixturewas stirred for 30 min in ice bath. A chilled solution of SnCl₂2H₂O (4.9g, 21.6 mmol) in 4 mL concentrate HCl was added dropwise. The mixturewas stirred for 30 min. It was chilled and filtered with a Buchnerfunnel to collect the solid hydrazine. The solid was dried in vacuuo. Itwas then dissolved in 50 mL glacial acetic acid. To it was added4,4,4-trifluoro-1-(2-furyl)-1,3-butanedione (2.18 g, 10.6 mmol). Themixture was refluxed for 2 hrs. The solvent was removed in vacuuo. Theresidue was taken into DCM. It was washed with water ×2, dried,concentrated and subjected to flash column to isolate3-trifluoromethyl-1-(3-fluoro-2-naphthyl)-5-(2-furyl)-1H-pyrazole (60%).Rf 0.52 (1:4 EtOAc:hexane). ES-MS: (M+H) 347.

[1335] Step 2. The above compound (1.10 g, 3.2 mmol) was dissolved in 30mL acetone. To it was added a solution of KMnO₄ (2.5 g, 16 mmol) in 30mL water. The mixture was stirred in 60° C. bath for 4 hrs. It wascooled and filtered through celite. The celite bed was thoroughly washedwith THF. The filtrate was concentrated in vacuuo to remove organicsolvent. The aqueous residue was acidified to pH 1 with 2M HCl. It wasextracted with EtOAc ×4. The organic phases were combined, washed withbrine, dried over MgSO₄, concentrated in vacuuo to afford isolate3-trifluoromethyl-1-(3-fluoro-2-naphthyl)-1H-pyrazole-5-carboxylic acid(55%). ES-MS: (M+H)⁺325.

[1336] Step 3. To a solution of2′-N-tert-butylaminosulfonyl-[1,1′]-biphenyl-4-ylamine (62 mg, 0.20mmol) and the above acid (44 mg, 0.14 mmol) in 8 mL pyridine in ice bathwas added POCl₃ (0.025 mL, 0.27 mmol). The mixture was stirred for 1 hr.Pyridine was removed in vacuuo. The organic residue was taken intoEtOAc, which was washed with brine and water. The organic solution wasdried and concentrated in vacuuo to yield the crude coupling product(65%). ES-MS: (M+H)⁺633. It was taken into 10 mL TFA. The mixture wasstirred for 5 hrs. It was evaporated in vacuuo and subjected to prepBPLC to give the title compound. ES-MS: (M+H)⁺555.

Example 171

[1337]

[1338] The title compound was prepared using the same methodologydescribed for Example 170, with 2′-N-tert-butylaminosulfonyl-3-fluoro-[1,1′]-biphenyl-4-ylamine substituted for2′-N-tert-butylaminosulfonyl-[1,1′]-biphenyl-4-ylamine. ES-MS:(M+H)⁺573.

Example 172

[1339]

[1340] The title compound was prepared using the same methodologydescribed for Example 170, with2′-N-tert-butylaminosulfonyl-3-chloro-[1,1′]-biphenyl-4-ylaminesubstituted for 2′-N-tert-butylaminosulfonyl-[1,1′]-biphenyl-4-ylamine.ES-MS: (M+H)⁺589.

Example 173

[1341]

[1342] The title compound was prepared using the same methodologydescribed for Example 170, with2-amino-5-(2-(N-tert-butylaminosulfonyl)phenyl)pyridine substituted for2′-N-tert-butylaminosulfonyl-[1,1′]-biphenyl-4-ylamine. ES-MS:(M+H)⁺556.

Example 174

[1343]

[1344] The title compound was prepared using the same methodologydescribed for Example 170, with2′-methylsulfonyl-[1,1′]-biphenyl-4-ylamine substituted for2′-N-tert-butylaminosulfonyl-[1,1′]-biphenyl-4-ylamine. ES-MS:(M+H)⁺554.

Example 175

[1345]

[1346] The title compound was prepared using the same methodologydescribed for Example 170, with2′-methylsulfonyl-3-fluoro-[1,1′]-biphenyl-4-ylamine substituted for2′-N-tert-butylaminosulfonyl-[1,1′]-biphenyl-4-ylamine. ES-MS:(M+H)⁺572.

Example 176

[1347]

[1348] The title compound was prepared using the same methodologydescribed for Example 16, with3-trifluoromethyl-1-(3-fluoro-2-naphthyl)-1H-pyrazole-5-carboxylic acidsubstituted for3-methyl-1-(3-fluoro-2-naphthyl)-1H-pyrazole-5-carboxylic acid. ES-MS:(M+H)⁺470.

Example 177

[1349]

[1350] The title compound was prepared using the same methodologydescribed for Example 14, with3-trifluoromethyl-1-(3-fluoro-2-naphthyl)-1H-pyrazole-5-carboxylic acidsubstituted for3-methyl-1-(3-fluoro-2-naphthyl)-1H-pyrazole-5-carboxylic acid. ES-MS:(M+H)⁺496.

Example 178

[1351]

[1352] The title compound was prepared using the same methodologydescribed for Example 15, with3-trifluoromethyl-1-(3-fluoro-2-naphthyl)-1H-pyrazole-5-carboxylic acidsubstituted for3-methyl-1-(3-fluoro-2-naphthyl)-1H-pyrazole-5-carboxylic acid. ES-MS:(M+H)⁺510.

Example 179

[1353]

[1354] The title compound was prepared using the same methodologydescribed for Example 13, with3-trifluoromethyl-1-(3-fluoro-2-naphthyl)-1H-pyrazole-5-carboxylic acidsubstituted for3-methyl-1-(3-fluoro-2-naphthyl)-1H-pyrazole-5-carboxylic acid. ES-MS:(M+H)⁺482.

Example 180

[1355]

[1356] The title compound was prepared using the same methodologydescribed for Example 162, with3-trifluoromethyl-1-(3-fluoro-2-naphthyl)-1H-pyrazole-5-carboxylic acidsubstituted for3-methyl-1-(3-fluoro-2-naphthyl)-1H-pyrazole-5-carboxylic acid. ES-MS:(M+H)⁺488.

Example 181

[1357]

[1358] The title compound was prepared using the same methodologydescribed for Example 23, with3-trifluoromethyl-1-(3-fluoro-2-naphthyl)-1H-pyrazole-5-carboxylic acidsubstituted for3-methyl-1-(3-fluoro-2-naphthyl)-1H-pyrazole-5-carboxylic acid. ES-MS:(M+H)⁺514.

Example 182

[1359]

[1360] The title compound was prepared using the same methodologydescribed for Example 24, with3-trifluoromethyl-1-(3-fluoro-2-naphthyl)-1H-pyrazole-5-carboxylic acidsubstituted for3-methyl-1-(3-fluoro-2-naphthyl)-1H-pyrazole-5-carboxylic acid. ES-MS:(M+H)⁺528.

Example 183

[1361]

[1362] The title compound was prepared using the same methodologydescribed for Example 22, with3-trifluoromethyl-1-(3-fluoro-2-naphthyl)-1H-pyrazole-5-carboxylic acidsubstituted for3-methyl-1-(3-fluoro-2-naphthyl)-1H-pyrazole-5-carboxylic acid. ES-MS:(M+H)⁺500.

Example 184

[1363]

[1364] The title compound was prepared using the same methodologydescribed for Example 180, with 2-amino-5-cyanopyridine substituted for4-amino-3-fluorobenzonitrile. ES-MS: (M+H)⁺471.

Example 185

[1365]

[1366] The title compound was prepared using the same methodologydescribed for Example 181, with 2-amino-5-cyanopyridine substituted for4-amino-3-fluorobenzonitrile. ES-MS: (M+H)⁺497.

Example 186

[1367]

[1368] The title compound was prepared using the same methodologydescribed for Example 182, with 2-amino-5-cyanopyridine substituted for4-amino-3-fluorobenzonitrile. ES-MS: (M+H)⁺511.

Example 187

[1369]

[1370] The title compound was prepared using the same methodologydescribed for Example 183, with 2-amino-5-cyanopyridine substituted for4-amino-3-fluorobenzonitrile. ES-MS: (M+H)⁺483.

Example 188

[1371]

[1372] The title compound was prepared using the same methodologydescribed for Example 184, with 3-methyl-1-(3-fluoro-2-naphthyl)-1H-pyrazole-5-carboxylic acid substituted for3-trifluoromethyl-1-(3-fluoro-2-naphthyl)-1H-pyrazole-5-carboxylic acid.ES-MS: (M+H)⁺417.

Example 189

[1373]

[1374] The title compound was prepared using the same methodologydescribed for Example 185, with3-methyl-1-(3-fluoro-2-naphthyl)-1H-pyrazole-5-carboxylic acidsubstituted for3-trifluoromethyl-1-(3-fluoro-2-naphthyl)-1H-pyrazole-5-carboxylic acid.ES-MS: (M+H)⁺443.

Example 190

[1375]

[1376] The title compound was prepared usinig the same methodologydescribed for Example 186 with3-methyl-1-(3-fluoro-2-naphthyl)-1H-pyrazole-5-carboxylic acidsubstituted for3-trifluoromethyl-1-(3-fluoro-2-naphthyl)-1H-pyrazole-5-carboxylic acid.ES-MS: (M+H)⁺457.

Example 191

[1377]

[1378] The title compound was prepared using the same methodologydescribed for Example 187, with3-methyl-1-(3-fluoro-2-naphthyl)-1H-pyrazole-5-carboxylic acidsubstituted for3-trifluoromethyl-1-(3-fluoro-2-naphthyl)-1H-pyrazole-5-carboxylic acid.ES-MS: (M+H)⁺429.

Example 192

[1379]

[1380] The title compound was prepared using the same methodology shownfor Example 91, with 6-chloro-2-naphthoic acid (Step 1, Example 115)substituted for 6-bromo-2-naphthoic acid. ES-MS: (M+H)⁺518.

Example 193

[1381]

[1382] The title compound was prepared using the same methodology shownfor Example 121, with 4-aminobenzonitrile substituted for4-amino-3-fluorobenzonitrile. ES-MS: (M+H)⁺432.

Example 194

[1383]

[1384] The title compound was prepared using the same methodology shownfor Example 119, with 4-aminobenzonitrile substituted for4-amino-3-fluorobenzonitrile. ES-MS: (M+H)⁻458.

Example 195

[1385]

[1386] The title compound was prepared using the same methodology shownfor Example 120, with 4-aminobenzonitrile substituted for4-amino-3-fluorobenzonitrile. ES-MS: (M+H)⁺472.

Example 196

[1387]

[1388] The title compound was prepared using the same methodology shownfor Example 118, with 4-aminobenzonitrile substituted for4-amino-3-fluorobenzonitrile. ES-MS: (M+H)⁺444.

Example 197

[1389]

[1390] The title compound was prepared using the same methodology shownfor Example 121, with 2-amino-5-cyanopyridine substituted for4-amino-3-fluorobenzonitrile. ES-MS: (M+H)⁺433.

Example 198

[1391]

[1392] The title compound was prepared using the same methodology shownfor Example 119, with 2-amino-5-cyanopyridine substituted for4-amino-3-fluorobenzonitrile. ES-MS: (M+H)⁺459.

Example 199

[1393]

[1394] The title compound was prepared using the same methodology shownfor Example 120, with 2-amino-5-cyanopyridine substituted for4-amino-3-fluorobenzonitrile. ES-MS: (M+H)⁺473.

Example 200

[1395]

[1396] The title compound was prepared using the same methodology shownfor Example 118, with 2-amino-5-cyanopyridine substituted for4-amino-3-fluorobenzonitrile. ES-MS: (M+H)⁺445.

Example 201

[1397]

[1398] Step 1. Preparation of 6-chloro-2-naphthylamine. It was preparedusing the same methodology shown for Step 1 and Step 2 of Example 85,with 6-chloro-2-naphthoic acid (Step 1, Example 115) substituted for6-bromo-2-naphthoic acid. ES-MS: (M+H)⁺178.

[1399] Step 2. The above amine (0.60 g, 3.47 mmol) was placed in 7 mLconcentrate HCl. The slurry was stirred in ice bath. To it was addeddropwise a chilled solution of sodium nitrite (0.26 g, 3.7 mmol) in 2 mLwater. After completion, the mixture was stirred for 30 min in ice bath.A chilled solution of SnCl₂.2H₂O (1.8 g, 8.2 mmol) in 3 mL concentrateHCl was added dropwise. The mixture was stirred for 30 min. It waschilled and filtered with a Buchner funnel to collect the solidhydrazine. The solid was dried in vacuuo. It was then dissolved in 50 mLglacial acetic acid. To it was added4,4,4-trifluoro-1-(2-furyl)-1,3-butanedione (0.70 g, 3.4 mmol). Themixture was refluxed for 2 hrs. The solvent was removed in vacuuo. Theresidue was taken into chloroform. It was washed with water ×2, dried,concentrated and subjected to flash column to isolate3-trifluoromethyl-1-(6-chloro-2-naphthyl)-5-(2-furyl)-1H-pyrazole (50%).Rf 0.77 (1:2 EtOAc:hexane). ES-MS: (M+H)⁺363.

[1400] Step 3. The above compound (150 mg, 0.41 mmol) was dissolved in 5mL acetone. To it was added a solution of KMnO₄ (327 mg, 2.1 mmol) in 2mL water. The mixture was stirred in 60° C. bath for 4 hrs. It wascooled and filtered through celite. The celite bed was thoroughly washedwith THF. The filtrate was concentrated in vacuuo to remove organicsolvent. The aqueous residue was acidified to pH 1 with 2M HCl. It wasextracted with EtOAc ×4. The organic phases were combined, washed withbrine, dried over MgSO₄, concentrated in vacuuo to afford isolate3-trifluoromethyl-1-(6-chloro-2-naphthyl)-1H-pyrazole-5-carboxylic acid(120 mg, 86%). ES-MS: (M+H)⁺341.

[1401] Step 4. To a solution of2′-N-tert-butylaminosulfonyl-[1,1′]-biphenyl-4-ylamine (72 mg, 0.24mmol) and the above acid (40 mg, 0.12 mmol) in 2 mL pyridine in ice bathwas added POCl₃ (0.045 mL, 0.48 mmol). The mixture was stirred for 1 hr.Pyridine was removed in vacuuo. The organic residue was taken intoEtOAc, which was washed with brine and water. The organic solution wasdried and concentrated in vacuuo to yield the crude coupling product(65%). ES-MS: (M+H)⁺649. It was taken into 5 mL TFA. The mixture wasstirred for 5 hrs. It was evaporated in vacuuo and subjected to prepHPLC to give the title compound. ES-MS: (M+H)⁺571.

Example 202

[1402]

[1403] The title compound was prepared using the same methodologydescribed for Example 201, with2′-N-tert-butylaminosulfonyl-3-fluoro-[1,1′]-biphenyl-4-ylaminesubstituted for 2′-N-tert-butylaminosulfonyl-[1,1′]-biphenyl-4-ylamine.ES-MS: (M+H)⁺589.

Example 203

[1404]

[1405] The title compound was prepared using the same methodologydescribed for Example 201, with2′-N-tert-butylaminosulfonyl-3-chloro-[1,1 ′]-biphenyl-4-ylaminesubstituted for 2′-N-tert-butylaminosulfonyl-[1,1′]-biphenyl-4-ylamine.ES-MS: (M+H)⁺605.

Example 204

[1406]

[1407] The title compound was prepared using the same methodologydescribed for Example 201,2-amino-5-(2-(N-tert-butylaminosulfonyl)phenyl)pyridine substituted for2′-N-tert-butylaminosulfonyl-[1,1′]-biphenyl-4-ylamine. ES-MS:(M+H)⁺572.

Example 205

[1408]

[1409] The title compound was prepared using the same methodology shownfor Example 193, with3-trifluoromethyl-1-(6-chloro-2-naphthyl)-1H-pyrazole-5-carboxylic acidsubstituted for3-methyl-1-(6-chloro-2-naphthyl)-1H-pyrazole-5-carboxylic acid. ES-MS:(M+H)⁺486.

Example 206

[1410]

[1411] The title compound was prepared using the same methodology shownfor Example 194, with3-trifluoromethyl-1-(6-chloro-2-naphthyl)-1H-pyrazole-5-carboxylic acidsubstituted for3-methyl-1-(6-chloro-2-naphthyl)-1H-pyrazole-5-carboxylic acid. ES-MS:(M+H)⁺512.

Example 207

[1412]

[1413] The title compound was prepared using the same methodology shownfor Example 195, with3-trifluoromethyl-1-(6-chloro-2-naphthyl)-1H-pyrazole-5-carboxylic acidsubstituted for3-methyl-1-(6-chloro-2-naphthyl)-1H-pyrazole-5-carboxylic acid. ES-MS:(M+H)⁺526.

Example 208

[1414]

[1415] The title compound was prepared using the same methodology shownfor Example 196 with3-trifluoromethyl-1-(6-chloro-2-naphthyl)-1H-pyrazole-5-carboxylic acidsubstituted for3-methyl-1-(6-chloro-2-naphthyl)-1H-pyrazole-5-carboxylic acid. ES-MS:(M+H)⁺498.

Example 209

[1416]

[1417] The title compound was prepared using the same methodology shownfor Example 205, with 4-amino-3-fluorobenzonitrile substituted for4-aminobenzonitrile. ES-MS: (M+H)⁺504.

Example 210

[1418]

[1419] The title compound was prepared using the same methodology shownfor Example 206, with 4-amino-3-fluorobenzonitrile substituted for4-aminobenzonitrile. ES-MS: (M+H)⁺530.

Example 211

[1420]

[1421] The title compound was prepared using the same methodology shownfor Example 207 with 4-amino-3-fluorobenzonitrile substituted for4-aminobenzonitrile. ES-MS: (M+H)⁺544.

Example 212

[1422]

[1423] The title compound was prepared using the same methodology shownfor Example 208 with 4-amino-3-fluorobenzonitrile substituted for4-aminobenzonitrile. ES-MS: (M+H)⁺516.

Example 213

[1424]

[1425] The title compound was prepared using the same methodology shownfor Example 205, with 2-amino-5-cyanopyridine substituted for4-aminobenzonitrile. ES-MS: (M+H)⁺487.

Example 214

[1426]

[1427] The title compound was prepared using the same methodology shownfor Example 206, with 2-amino-5-cyanopyridine substituted for4-aminobenzonitrile. ES-MS: (M+H)⁺513.

Example 215

[1428]

[1429] The title compound was prepared using the same methodology shownfor Example 207, with 2-amino-5-cyanopyridine substituted for4-aminobenzonitrile. ES-MS: (M+H)⁺527.

Example 216

[1430]

[1431] The title compound was prepared using the same methodology shownfor Example 208, with 2-amino-5-cyanopyridine substituted for4-aminobenzonitrile. ES-MS: (M+H)⁺499.

Example217

[1432]

[1433] The title compound was prepared using the same methodology shownfor Example 117, with 2′-methylsulfonyl-[1,1′]-biphenyl-4-ylaminesubstituted for 2′-methylsulfonyl-3-fluoro-[1,1′]-biphenyl-4-ylamine.ES-MS: (M+H)⁺516.

Example 218

[1434]

[1435] Step 1. 6-Amino-2-naphthoic acid (10.5 g, 56 mmol) was placed in56 mL concentrate HCl. At 0° C. to this vigorously stirred slurry addeda cold solution of sodium nitrite (4.6 g, 67 mmol) in 10 mL water. Aftercompletion, the mixture was stirred for 30 min in the cold bath.Tetrafluoroboric (48%, 15 mL, 112 mmol) was chilled and added to thereaction mixture. The slurry was stirred in the cold bath for 30 min andfiltered through a cold Buchner funnel to collect the solid. The cakewas washed with cold tetrafluoroboric acid (10 mL ×2). The solid wasdried in vacuuo.

[1436] Step 2. The above solid was taken into 200 mL toluene. Thesuspension was refluxed for overnight. Toluene was removed in vacuuo. Toresidue was taken into 2N HCl. It was extracted with EtOAc ×3. Theorganic phases were combined, washed with brine, dried, concentrated invacuuo to afford 6-fluoro-2-naphthoic acid (9.5 g, 89%). ES-MS:(M+Na)⁺213.

[1437] Step 3. The above acid was placed in 100 mL dry DCM with 0.5 mLDMF. To it was added oxalyl chloride (15 mL, 168 mmol) dropwise. Themixture was stirred for overnight. It was concentrated in vacuuo. Thedry acid chloride was then dissolved in 200 mL dry dioxane. It waschilled in ice bath and vigorously stirred. To it was dropwise added acold solution of sodium azide (7.3 g, 112 mmol) in 30 mL water and 30 mLdioxane. The reaction was stirred for 2 hrs. After evaporation invacuuo, the residue was taken into 300 mL DCM. It was washed with water×3 and then evaporated in vacuuo. The residue was dissolved in 120 mLDMF. To it was added 60 mL water. The mixture was refluxed for 6 hrs.The solvent was removed in vacuuo. The residue was taken intochloroform, washed with water, dried, concentrated in vacuuo to give6-fluoro-2-naphthylamine (50%). Rf 0.53 (1:1 EtOAc:hexane). ES-MS:(M+H)⁺162.

[1438] Step 4. The title compound was prepared using the samemethodology shown for Example 115, with 6-fluoro-2-naphthylaminesubstituted for 6-chloro-2-naphthylamine. ES-MS: (M+H)⁺501.

Example 219

[1439]

[1440] The title compound was prepared using the same methodology shownfor Example 218, with2′-N-tert-butylaminosulfonyl-3-fluoro-[1,1′]-biphenyl-4-ylaminesubstituted for 2′-Ntert-butylaminosulfonyl-[1,1 ′]-biphenyl-4-ylamine.ES-MS: (M+H)⁺519.

Example 220

[1441]

[1442] The title compound was prepared using the same methodology shownfor Example 218, with 2′-methylsulfonyl-[1,1′]-biphenyl-4-ylaminesubstituted for 2′-N-tert-butylaminosulfonyl-[1,1′]-biphenyl-4-ylamine.ES-MS: (M+H)⁺500.

Example 221

[1443]

[1444] The title compound was prepared using the same methodology shownfor Example 218, with2′-methylsulfonyl-3-fluoro-[1,1′]-biphenyl-4-ylamine substituted for2′-N-tert-butylaminosulfonyl-[1,1′]-biphenyl-4-ylamine. ES-MS:(M+H)⁺518.

Example 222

[1445]

[1446] The title compound was prepared using the same methodology shownfor Example 193, with 6-fluoro-2-naphthylamine substituted for6-chloro-2-naphthylamine. ES-MS: (M+H)⁻416.

Example 223

[1447]

[1448] The title compound was prepared using the same methodology shownfor Example 194, with 6-fluoro-2-naphthylamine substituted for6-chloro-2-naphthylamine. ES-MS: (M+H)⁺442.

Example 224

[1449]

[1450] The title compound was prepared using the same methodology shownfor Example 195, with 6-fluoro-2-naphthylamine substituted for6-chloro-2-naphthylarmine. ES-MS: (M+H)⁺456.

Example 225

[1451]

[1452] The title compound was prepared using the same methodology shownfor Example 196, with 6-fluoro-2-naphthylamine substituted for6-chloro-2-naphthylamine. ES-MS: (M+H)⁺428.

Example 226

[1453]

[1454] The title compound was prepared using the same methodology shownfor Example 121, with 6-fluoro-2-naphthylamine substituted for6-chloro-2-naphthylamine. ES-MS: (M+H)⁺434.

Example 227

[1455]

[1456] The title compound was prepared using the same methodology shownfor Example 119, with 6-fluoro-2-naphthylamine substituted for6-chloro-2-naphthylamine. ES-MS: (M+H)⁺460.

Example 228

[1457]

[1458] The title compound was prepared using the same methodology shownfor Example 120, with 6-fluoro-2-naphthylamine substituted for6-chloro-2-naphthylamine. ES-MS: (M+H)⁺474.

Example 229

[1459]

[1460] The title compound was prepared using the same methodology shownfor Example 118, with 6-fluoro-2-naphthylamine substituted for6-chloro-2-naphthylamine. ES-MS: (M+H)⁺446.

Example 230

[1461]

[1462] This compound was prepared by the same methodology described forExample 64 with for 2′-methylsulfonyl-3-fluoro-[1,1′]-biphenyl-4-ylaminesubstituted for 2′-methylsulfonyl-[1,1′]-biphenyl-4-ylamine, without thefinal TFA treatment. ES-MS: (M+H)⁺578.

Example 231

[1463]

[1464] This compound was prepared by the same methodology described forExample 81 with 4-aminobenzonitrile substituted for4-amino-3-fluorobenzonitrile. ES-MS: (M+H)⁺476.

Example 232

[1465]

[1466] This compound was prepared by the same methodology described forExample 231 with piperidine substituted for N-methylethylenediamine.ES-MS: (M+H)⁺516.

Example 233

[1467]

[1468] This compound was prepared by the same methodology described forExample 231 with thiomorpholine substituted for N-methylethylenediamine.ES-MS: (M+H)⁺534.

Example 234

[1469]

[1470] This compound was prepared by the same methodology described forExample 69 with 1-(4-aminophenyl)-4-methylhomopiperazine substituted forwith 1-(4-aminophenyl)-4-methylpiperazine. ES-MS: (M+H)⁺490.

Example 235

[1471]

[1472] Step 1. Preparation of3-methyl-1-(3-methylsulfonyl-2-naphthyl)-1H-pyrazole-5-carboxylic acid.It is described in the Step 2 of Example 59.

[1473] Step 2. The above acid (1.28 g, 3.88 mmol) was dissolved in 40 mLdry THF and chilled in ice bath. To it was added LiHMDS (1M, 15.5 mL,15.5 mmol) dropwise. The mixture was stirred for 30 min. Chilled in theice bath, to it was added Bu₃B (1M, 20 mL, 20 mmol) dropwise. After 2hrs, the mixture was refluxed for 2.5 hrs. It was cooled and placed inice bath. To it were added sodium acetate (3.2 g, 39 mmol), water (200mL) and H₂NOSO₃H (3.5 g, 31 mmol). The mixture was stirred forovernight. It was concentrated in vacuuo. The aqueous residue wasacidified to pH 1 with 5N HCL. It was extracted with EtOAc ×4. Theorganic phases were combined, dried over MgSO₄, evaporated in vacuuo toafford 3-methyl-1-(3-aminosulfonyl-2-naphthyl)-1H-pyrazole-5-carboxylicacid (85%). ES-MS: (M+H)⁺332.

[1474] Step 3. The title compound was prepared by the same methodologydescribed for Example 59, with3-methyl-1-(3-aminosulfonyl-2-naphthyl)-1H-pyrazole-5-carboxylic acidsubstituted for3-methyl-1-(3-methylsulfonyl-2-naphthyl)-1H-pyrazole-5-carboxylic acid,and also with 2′-N-tert-butylaminosulfonyl-[1,1′]-biphenyl-4-ylaminesubstituted for2′-N-tert-butylaminosulfonyl-3-fluoro-[1,1′]-biphenyl-4-ylamine. ES-MS:(M+H)⁺562.

Examle 236

[1475]

[1476] The title compound was prepared by the same methodology describedfor Example 235, with2′-N-tert-butylaminosulfonyl-3-fluoro-[1,1′]-biphenyl-4-ylaminesubstituted for 2′-N-tert-butylaminosulfonyl-[1,1 ′]-biphenyl-4-ylanine.ES-MS: (M+H)⁺580.

Example 237

[1477]

[1478] The title compound was prepared by the same methodology describedfor Example 235, with2-amino-5-(2-(N-tert-butylaminosulfonyl)phenyl)pyridine substituted for2′-N-tert-butylaminosulfonyl-[1,1′]-biphenyl-4-ylamine. ES-MS:(M+H)⁺563.

Example 238

[1479]

[1480] The title compound was prepared by the same methodology describedfor Example 235, with 2′-methylsulfonyl-[1,1′]-biphenyl-4-ylaminesubstituted for 2′-N-tert-butylaminosulfonyl-[1,1′]-biphenyl-4-ylamine.ES-MS: (M+H)⁺561.

Example 239

[1481]

[1482] The title compound was prepared by the same methodology describedfor Example 235, with2′-methylsulfonyl-3-fluoro-[1,1′]-biphenyl-4-ylamine substituted for2′-N-tert-butylaminosulfonyl-[1,1′]-biphenyl-4-ylamine. ES-MS:(M+H)⁺579.

Example 240

[1483]

[1484] The title compound was prepared using the same methodology shownfor Example 16, with 3-methyl-1-(3-aminosulfonyl-2-naphthyl)-1H-pyrazole-5-carboxylic acid substituted for3-methyl-1-(3-fluoro-2-naphthyl)-1H-pyrazole-5-carboxylic acid. ES-MS:(M+H)⁺477.

Example 241

[1485]

[1486] The title compound was prepared using the same methodology shownfor Example 14, with3-methyl-1-(3-aminosulfonyl-2-naphthyl)-1H-pyrazole-5-carboxylic acidsubstituted for3-methyl-1-(3-fluoro-2-naphthyl)-1H-pyrazole-5-carboxylic acid. ES-MS:(M+H)⁺503.

Example 242

[1487]

[1488] The title compound was prepared using the same methodology shownfor Example 15, with3-methyl-1-(3-aminosulfonyl-2-naphthyl)-1H-pyrazole-5-carboxylic acidsubstituted for3-methyl-1-(3-fluoro-2-naphthyl)-1H-pyrazole-5-carboxylic acid. ES-MS:(M+H)⁺517.

Example 243

[1489]

[1490] The title compound was prepared using the same methodology shownfor Example 13, with3-methyl-1-(3-aminosulfonyl-2-naphthyl)-1H-pyrazole-5-carboxylic acidsubstituted for3-methyl-1-(3-fluoro-2-naphthyl)-1H-pyrazole-5-carboxylic acid. ES-MS:(M+H)⁺489.

Example 244

[1491]

[1492] The title compound was prepared using the same methodology shownfor Example 240, with 4-amino-3-fluorobenzonitrile substituted for4-aminobenzonitrile. ES-MS: (M+H)⁺495.

Example 245

[1493]

[1494] The title compound was prepared using the same methodology shownfor Example 241, with 4-amino-3-fluorobenzonitrle substituted for4-aminobenzonitrile. ES-MS: (M+H)⁺521.

Example 246

[1495]

[1496] The title compound was prepared using the same methodology shownfor Example 242, with 4-amino-3-fluorobenzonitrile substituted for4-aminobenzonitrile. ES-MS: (M+H)⁺535.

Example 247

[1497]

[1498] The title compound was prepared using the same methodology shownfor Example 243, with 4-amino-3-fluorobenzonitrile substituted for4-aminobenzonitrile. ES-MS: (M+H)⁺507.

Example 248

[1499]

[1500] Step 1. 2-Nitronaphthalyene (7.0 g, 40 mmol) was dissolved in 200mL ethanol. To it was added SnCl₂.2H₂O (27.4 g, 121 mmol). The mixturewas refluxed for 2.5 hrs. It was concentrated in vacuuo. The residue wastaken into DCM, washed with water ×3, dried, evaporated in vacuuo togive 2-aminonaphthalene (90%). ES-MS: (M+H)⁺144.

[1501] Step 2. The above amine (1.0 g, 7 mmol) was placed in 3 mL TFA.Chilled by ice bath, to it was added sodium nitrite (0.53 g, 7.7 mmol)in small portions. The mixture was stirred in the bath for 45 min. Achilled solution of sodium azide (0.46 g, 7 mmol) in 1 mL water wasadded dropwise. The mixture was stirred for 45 min. The reaction wasdiluted with a cold saturated sodium carbonate aqueous solution. It wasextracted with DCM ×2. The combined organic phase was dried, evaporatedin vacuuo, purified using flash column to give 2-azidonaphthalene (0.69g, 58%). Rf 0.78 (1:7 EtOAc:hexane).

[1502] Step 3.The above compound (0.38 g, 2.2 mmol) was dissolved in 5mL toluene. To it was added ethyl propiolate (1.1 mL, 11 mmol). Themixture was refluxed for 1.5 hr. It was concentrated in vacuuo andsubjected to flash column purification to give a pair of isomers. Ethyl1-(2-naphthyl)-1,2,3-triazole-5-carboxylate, 200 mg, Rf 0.60 (1:1EtOAc:hexane), ES-MS: (M+H)⁺268. Ethyl1-(2-naphthyl)-1,2,3-triazole-4-carboxylate, 400 mg, Rf 0.50 (1:1EtOAc:hexane), ES-MS: (M+H)⁺268.

[1503] Step 4. The mixture of ethyl1-(2-naphthyl)-1,2,3-triazole-5-carboxylate (70 mg, 0.26 mmol) and2′-N-tert-butylaminosulfonyl-[1,1′]-biphenyl-4-ylamine (120 mg, 0.39mmol) was dissolved in 5 mL dry DCM. To it was added trimethylaluminum(2M, 0.7 mL, 1.4 mmol). The mixture was stirred for overnight. It wasquenched with aqueous Rochelle's salt solution. It was extracted withDCM ×3. The organic phases were combined, dried, evaporated in vacuuo.The residue was taken into 5 mL TFA and stirred for 6 hrs. It wasconcentrated in vacuuo and purified using HPLC to afford the titlecompound in about 60% yield. ES-MS: (M+H)⁺470.

Example 249

[1504]

[1505] The title compound was prepared using the same methodology shownfor Example 248, with 2′-N-tert-butylaminosulfonyl-3-fluoro-[1,1′]-biphenyl-4-ylamine substituted for2′-N-tert-butylaminosulfonyl-[1,1′]-biphenyl-4-ylamine. ES-MS:(M+H)⁺488.

Example 250

[1506]

[1507] The title compound was prepared using the same methodology shownfor Example 16, with ethyl 1-(2-naphthyl)-1,2,3-triazole-5-carboxylatesubstituted for3-methyl-1-(3-fluoro-2-naphthyl)-1H-pyrazole-5-carboxylic acid. ES-MS:(M+H)⁺385.

Example 251

[1508]

[1509] The title compound was prepared using the same methodology shownfor Example 250, with pyrrolidine substituted for dimethylamine. ES-MS:(M+H)⁺411.

Example 252

[1510]

[1511] The title compound was prepared using the same methodology shownfor Example 250, with piperidine substituted for dimethylamine. ES-MS:(M+H)⁺425.

Example 253

[1512]

[1513] The title compound was prepared using the same methodology shownfor Example 250, with N-methylethylenediamine substituted fordimethylamine. ES-MS: (M+H)⁺397.

Example 254

[1514]

[1515] Step 1. 2-Aminonaphthalene (Step 1, Example 248, 1.02 g, 7.1mmol) was dissolved in 20 mL DCM. To it were added triethylamine (4 mL)and then ethyl oxalyl chloride (0.95 mL, 8.6 mmol) dropwise. Thereaction was stirred for 3 hrs. It was concentrated in vacuuo. Theresidue was taken into DCM, washed with water ×2, dried over MgSO₄,evaporated in vacuuo to afford the amide in quantitative yield. Rf 0.68(1:1 EtOAc:hexane). ES-MS: (M+H)⁺244.

[1516] Step 2. The above amide (1.46 g, 6 mmol) was dissolved in CCl₄(30 mL). To it was added a solution of Ph₃P (3.24 g, 12 mmol) in CCl₄(20 mL). The resulting mixture was refluxed for 22 hrs. It was cooledand filtered through a silica plug. The filtrate was evaporated invacuuo to give the iminoyl chloride in high yield (>90%). ES-MS:(M+H)⁺262. This crude iminoyl chloride was dissolved in 40 mL MeCN. Toit was added sodium azide (0.47 g, 7.2 mmol). It was stirred for 3 hrsat room temperature. It was concentrated in vacuuo. The residue wastaken into EtOAc, washed with water ×2, dried, evaporated, purified withflash column to give ethyl 1-(2-naphthyl)-tetrazole-5-carboxylate (70%).Rf 0.69 (1:1 EtOAc:hexane). ES-MS: (M+H)⁺269.

[1517] Step 3. The mixture of ethyl1-(2-naphthyl)-tetrazole-5-carboxylate (50 mg, 0.19 mmol) and2′-N-tert-butylaminosulfonyl-[1,1′]-biphenyl-4-ylamine (85 mg, 0.28mmol) was dissolved in 5 mL dry DCM. To it was added trimethylaluminum(2M, 0.5 mL, 1.0 mmol). The mixture was stirred for overnight. It wasquenched with aqueous Rochelle's salt solution. It was extracted withDCM ×3. The organic phases were combined, dried, evaporated in vacuuo.The residue was taken into 5 mL TFA and stirred for 6 hrs. It wasconcentrated in vacuuo and purified using HPLC to afford the titlecompound in about 60% yield. ES-MS: (M+H)⁺471.

Example 255

[1518]

[1519] The title compound was prepared using the same methodology shownfor Example 254, with2′-N-tert-butylaminosulfonyl-3-fluoro-[1,1′]-biphenyl-4-ylaminesubstituted for 2′-N-tert-butylaminosulfonyl-[1,1′]-biphenyl-4-ylamine.ES-MS: (M+H)⁺489.

Example 256

[1520]

[1521] The title compound was prepared using the same methodology shownfor Example 254, with2′-methylsulfonyl-3-fluoro-[1,1′]-biphenyl-4-ylamine substituted for2′-N-tert-butylaminosulfonyl-[1,1′]-biphenyl-4-ylamine. ES-MS:(M+H)⁺488.

Example 257

[1522]

[1523] The title compound was prepared using the same methodology shownfor Example 16, with ethyl 1-(2-naphthyl)-tetrazole-5-carboxylatesubstituted for3-methyl-1-(3-fluoro-2-naphthyl)-1H-pyrazole-5-carboxylic acid. ES-MS:(M+H)⁺386.

Example 258

[1524]

[1525] The title compound was prepared using the same methodology shownfor Example 257, with pyrrolidine substituted for dimethylamnine. ES-MS:(M+H)⁺412.

Example 259

[1526]

[1527] The title compound was prepared using the same methodology shownfor Example 257, with piperidine substituted for dimethylamine. ES-MS:(M+H) 426.

Example 260

[1528]

[1529] The title compound was prepared using the same methodology shownfor Example 257, with N-methylethylenediamine substituted fordimethylamine. ES-MS: (M+H)⁺398.

Example 261

[1530]

[1531] The title compound was prepared using the same methodology shownfor Example 257, with thiomorpholine substituted for dimethylamine.ES-MS: (M+H)⁺444.

Example 262

[1532]

[1533] The title compound was prepared using the same methodology shownfor Example 257, with 4-amino-3-fluorobenzonitrile substituted for4-aminobenzonitrile. ES-MS: (M+H)⁺404.

Example 263

[1534]

[1535] The title compound was prepared using the same methodology shownfor Example 258, with 4-amino-3-fluorobenzonitrile substituted for4-aminobenzonitrile. ES-MS: (M+H)⁺430.

Example 264

[1536]

[1537] The title compound was prepared using the same methodology shownfor Example 259, with 4-amino-3-fluorobenzonitrile substituted for4-aminobenzonitrile. ES-MS: (M+H)⁺444.

Example 265

[1538]

[1539] The title compound was prepared using the same methodology shownfor Example 260, with 4-amino-3-fluorobenzonitrile substituted for4-aminobenzonitrile. ES-MS: (M+H)⁺416.

Example 266

[1540]

[1541] The title compound was prepared using the same methodology shownfor Example 254, with 3-fluoro-2-naphthylamine (Step 2, Example 3)substituted for 2-naphthylamine. ES-MS: (M+H)⁺489.

Example 267

[1542]

[1543] The title compound was prepared using the same methodology shownfor Example 266, with 2′-methylsulfonyl-[1,1′]-biphenyl-4-ylaminesubstituted for 2′-N-tert-butylaminosulfonyl-[1,1′]-biphenyl-4-ylamine.ES-MS: (M+H)⁺488.

Example 268

[1544]

[1545] The title compound was prepared using the same methodology shownfor Example 266, with2-amino-5-(2-(N-tert-butylaminosulfonylphenyl)pyridine substituted for2′-N-tert-butylaminosulfonyl-[1,1′]-biphenyl-4-ylamine. ES-MS:(M+H)⁺490.

Example 269

[1546]

[1547] The title compound was prepared using the same methodology shownfor Example 266, with2′-N-tert-butytaminosulfonyl-3-fluoro-[1,1′]-biphenyl-4-ylaminesubstituted for 2′-N-tert-butylaminosulfonyl-[1,1′]-biphenyl-4-ylamine.ES-MS: (M+H)⁺507.

Example 270

[1548]

[1549] The title compound was prepared using the same methodology shownfor Example 266, with2′-methylsulfonyl-3-fluoro-[1,1′]-biphenyl-4-ylamine substituted for2′-N-tert-butylaminosulfonyl-[1,1′]-biphenyl-4-ylamine. ES-MS:(M+H)⁺506.

Example 271

[1550]

[1551] The title compound was prepared using the same methodology shownfor Example 266, with 2′-N-tert-butylaminosulfonyl-3-chloro-[1,1′]-biphenyl-4-ylamine substituted for2′-N-tert-butylaminosulfonyl-[1,1′]-biphenyl-4-ylamine. ES-MS:(M+H)⁺523.

Example 272

[1552]

[1553] The title compound was prepared using the same methodology shownfor Example 257, with 3-fluoro-2-naphthylamine substituted for2-naphthylamine. ES-MS: (M+H)⁺404.

Example 273

[1554]

[1555] The title compound was prepared using the same methodology shownfor Example 258, with 3-fluoro-2-naphthylamine substituted for2-naphthylamine. ES-MS: (M+H)⁺430.

Example 274

[1556]

[1557] The title compound was prepared using the same methodology shownfor Example 259, with 3-fluoro-2-naphthylamine substituted for2-naphthylamine. ES-MS: (M+H)⁺444.

Example 275

[1558]

[1559] The title compound was prepared using the same methodology shownfor Example 260, with 3-fluoro-2-naphthylamine substituted for2-naphthylamine. ES-MS: (M+H)⁺416.

Example 276

[1560]

[1561] The title compound was prepared using the same methodology shownfor Example 262, with 3-fluoro-2-naphthylamine substituted for2-naphthyl amine. ES-MS: (M+H)⁺422.

Example 277

[1562]

[1563] The title compound was prepared using the same methodology shownfor Example 263, with 3-fluoro-2-naphthylamine substituted for2-naphthylamine. ES-MS: (M+H)⁺448.

Example 278

[1564]

[1565] The title compound was prepared using the same methodology shownfor Example 264, with 3-fluoro-2-naphthylamine substituted for2-naphthylamine. ES-MS: (M+H)⁺462.

Example 279

[1566]

[1567] The title compound was prepared using the same methodology shownfor Example 265, with 3-fluoro-2-naphthylamine substituted for2-naphthylamine. ES-MS: (M+H)⁺434.

Example 280

[1568]

[1569] The title compound was prepared using the same methodology shownfor Example 254, with 6-fluoro-2-naphthylamine (Step 3, Example 218)substituted for 2-naphthylamine. ES-MS: (M+H)⁺489.

Example 281

[1570]

[1571] The title compound was prepared using the same methodology shownfor Example 267, with 6-fluoro-2-naphthylamine substituted for3-fluoro-2-naphthylamine. ES-MS: (M+H)⁺488.

Example 282

[1572]

[1573] The title compound was prepared using the same methodology shownfor Example 269, with 6-fluoro-2-naphthylamine substituted for3-fluoro-2-naphthylamine. ES-MS: (M+H)⁺507.

Example 283

[1574]

[1575] The title compound was prepared using the same methodology shownfor Example 270, with 6-fluoro-2-naphthylamine substituted for3-fluoro-2-naphthylamine. ES-MS: (M+H)⁺506.

Example 284

[1576]

[1577] The title compound was prepared using the same methodology shownfor Example 272, with 6-fluoro-2-naphthylamine substituted for3-fluoro-2-naphthylamine. ES-MS: (M+H)⁺404.

Example 285

[1578]

[1579] The title compound was prepared using the same methodology shownfor Example 273, with 6-fluoro-2-naphthylamine substituted for3-fluoro-2-naphthylamine. ES-MS: (M+H)⁺430.

Example 286

[1580]

[1581] The title compound was prepared using the same methodology shownfor Example 274, with 6-fluoro-2-napthylamine substituted for3-fluoro-2-naphthylamine. ES-MS: (M+H)⁺444.

Example 287

[1582]

[1583] The title compound was prepared using the same methodology shownfor Example 275, with 6-fluoro-2-naphthylamine substituted for3-fluoro-2-naphthylamine. ES-MS: (M+H)⁺416.

Example 288

[1584]

[1585] The title compound was prepared using the same methodology shownfor Example 276, with 6-fluoro-2-naphthylamine substituted for3-fluoro-2-naphthylamine. ES-MS: (M+H)⁺422.

Examle 289

[1586]

[1587] The title compound was prepared using the same methodology shownfor Example 277, with 6-fluoro-2-naphthylamine substituted for3-fluoro-2-naphthylamine. ES-MS: (M+H)⁺448.

Example 290

[1588]

[1589] The title compound was prepared using the same methodology shownfor Example 278, with 6-fluoro-2-naphthylamine substituted for3-fluoro-2-naphthylamine. ES-MS: (M+H)⁺462.

Example 291

[1590]

[1591] The title compound was prepared using the same methodology shownfor Example 279, with 6-fluoro-2-naphthylamine substituted for3-fluoro-2-naphthylamine. ES-MS: (+H)⁺434.

Example 292

[1592]

[1593] Step 1. Preparation of 6-chloro-2-naphthoic acid is described inStep 1, Example 115.

[1594] Step 2. The above acid (6.57 g, 32 mmol) was stirred in 200 mLdry DCM with 0.5 mL DMF. To it was added dropwise oxalyl chloride (8.4mL, 96 mmol). The reaction was stirred for 2 hrs. It was evaporated invacuuo to dryness. The residue was taken into 300 mL dry dioxane. It wasstirred in ice bath. To this solution was added dropwise a cold solutionof sodium azide (4.2 g, 64 mmol) in 15 mL water and 15 mL dioxane. Aftercompletion, the mixture was stirred for 1 hr. It was then concentratedin vacuuo to remove dioxane. The residue was taken into chloroform andwashed with water ×2. The organic phase was dried, evaporated in vacuuo.It was dissolved in 160 mL DMF. To it was added 80 mL water. The mixturewas refluxed for 5 hrs. It was concentrated in vacuuo to remove waterand DMF. The residue was taken into 400 mL chloroform, washed with water×2, dried, evaporated in vacuuo to dryness to afford6-chloro-2-naphthylamine (90%). ES-MS: (M+H)⁺178.

[1595] Step 3. The title compound was prepared using the samemethodology shown for Example 254, with 6-chloro-2-naphthylaminesubstituted for 2-naphthylamine. ES-MS: (M+H)⁺505.

Example 293

[1596]

[1597] The title compound was prepared using the same methodology shownfor Example 267, with 6-chloro-2-naphthylamine substituted for3-fluoro-2-naphthylamine. ES-MS (M+H)⁺504.

Example 294

[1598]

[1599] The title compound was prepared using the same methodology shownfor Example 269, with 6-chloro-2-naphthylamine substituted for3-fluoro-2-naphthylamine. ES-MS: (M+H)⁺523.

Example 295

[1600]

[1601] The title compound was prepared using the same methodology shownfor Example 270, with 6-chloro-2-naphthyl amine substituted for3-fluoro-2-naphthylamine. ES-MS: (M+H)⁺522.

Example 296

[1602]

[1603] The title compound was prepared using the same methodology shownfor Example 272, with 6-chloro-2-naphthylamine substituted for3-fluoro-2-naphthylamine. ES-MS: (M+H)⁺420.

Example 297

[1604]

[1605] The title compound was prepared using the same methodology shownfor Example 273, with 6-chloro-2-naphthylamine substituted for3-fluoro-2-naphthylamine. ES-MS: (M+H)⁺446.

Example 298

[1606]

[1607] The title compound was prepared using the same methodology shownfor Example 274, with 6-chloro-2-naphthylamine substituted for3-fluoro-2-naphthylamine. ES-MS: (M+H)⁺460.

Example 299

[1608]

[1609] The title compound was prepared using the same methodology shownfor Example 275, with 6-chloro-2-naphthylamine substituted for3-fluoro-2-naphthylamine. ES-MS: (M+H)⁺432.

Example 300

[1610]

[1611] The title compound was prepared using the same methodology shownfor Example 276, with 6-chloro-2-naphthylamine substituted for3-fluoro-2-naphthylamine. ES-MS: (M+H)⁺438.

Example 301

[1612]

[1613] The title compound was prepared using the same methodology shownfor Example 277, with 6-chloro-2-naphthylamine substituted for3-fluoro-2-naphthylamine. ES-MS: (M+H)⁺464.

Example 302

[1614]

[1615] The title compound was prepared using the same methodology shownfor Example 278, with 6-chloro-2-naphthylamine substituted for3-fluoro-2-naphthylamine. ES-MS: (M+H)⁺478.

Example 303

[1616]

[1617] The title compound was prepared using the same methodology shownfor Example 279, with 6-chloro-2-naphthylamine substituted for3-fluoro-2-naphthylamine. ES-MS: (M+H)⁺450.

Example 304

[1618]

[1619] The title compound was prepared using the same methodology shownfor Example 254, with 6-bromo-2-naphthylamine (Step 2, Example 85)substituted for 2-naphthylamine. ES-MS: (M+H)⁺549, 551 (Br pattern).

Example 305

[1620]

[1621] The title compound was prepared using the same methodology shownfor Example 267, with 6-bromo-2-naphthylamine substituted for3-fluoro-2-naphthylamine. ES-MS: (M+H)⁺548, 550 (Br pattern).

Examnple 306

[1622]

[1623] The title compound was prepared using the same methodology shownfor Example 269, with 6-bromo-2-naphthylamine substituted for3-fluoro-2-naphthylamine. ES-MS: (M+H)⁺567, 569 (Br pattern).

Example 307

[1624]

[1625] The title compound was prepared using the same methodology shownfor Example 270, with 6-bromo-2-naphthylamine substituted for3-fluoro-2-naphthylamine. ES-MS: (M+H)⁺566, 568 (Br pattern).

Example 308

[1626]

[1627] The title compound was prepared using the same methodology shownfor Example 272, with 6-bromo-2-naphthylamine substituted for3-fluoro-2-naphthylamine. ES-MS: (M+H)⁺464, 466 (Br pattern).

Example 309

[1628]

[1629] The title compound was prepared using the same methodology shownfor Example 273, with 6-bromo-2-naphthylamine substituted for3-fluoro-2-naphthylamine. ES-MS: (M+H)⁺490, 492 (Br pattern).

Example 310

[1630]

[1631] The title compound was prepared using the same methodology shownfor Example 274, with 6-bromo-2-naphthylamine substituted for3-fluoro-2-naphthylamine. ES-MS: (M+H)⁺504, 506 (Br pattern).

Example 311

[1632]

[1633] The title compound was prepared using the same methodology shownfor Example 275, with 6-bromo-2-naphthylamine substituted for3-fluoro-2-naphthylamine. ES-MS: (M+H)⁺476, 478 (Br pattern).

Example 312

[1634]

[1635] The title compound was prepared using the same methodology shownfor Example 276, with 6-bromo-2-naphthylamine substituted for3-fluoro-2-naphthylamine. ES-MS: (M+H)⁺482, 484 (Br pattern).

Example 313

[1636]

[1637] The title compound was prepared using the same methodology shownfor Example 277, with 6-bromo-2-naphthylamine substituted for3-fluoro-2-naphthylamine. ES-MS: (M+H)⁺508, 510 (Br pattern).

Example 314

[1638]

[1639] The title compound was prepared using the same methodology shownfor Example 278, with 6-bromo-2-naphthylamine substituted for3-fluoro-2-naphthylainine. ES-MS: (M+H)⁺522, 524 (Br pattern).

Example 315

[1640]

[1641] The title compound was prepared using the same methodology shownfor Example 279, with 6-bromo -2-naphthyl amine substituted for3-fluoro-2-naphthylamine. ES-MS: (M+H)⁺494, 496 (Br pattern).

Example 316

[1642]

[1643] The title compound was prepared using the same methodology shownfor Example 15, with isonipecotic acid substituted for piperidine. ES-MS(M+H)⁺500.

Example 317

[1644]

[1645] The title compound was prepared using the same methodology shownfor Example 24, with isonipecotic acid substituted for piperidine.ES-MS: (M+H)⁺518.

Example 318

[1646]

[1647] The title compound was prepared using the same methodology shownfor Example 15, with isonipecotamide substituted for piperidine. ES-MS:(M+H)⁺499.

Example 319

[1648]

[1649] The title compound was prepared using the same methodology shownfor Example 24, with isonipecotictamide substituted for piperidine.ES-MS: (M+H)⁺517.

Example 320

[1650]

[1651] The title compound was prepared using the same methodology shownfor Example 274, with isonipecotic acid substituted for piperidine.ES-MS: (M+H)⁺488.

Example 321

[1652]

[1653] The title compound was prepared using the same methodology shownfor Example 278, with isonipecotic acid substituted for piperidine.ES-MS: (M+H)⁺506.

Example 322

[1654]

[1655] The title compound was prepared using the same methodology shownfor Example 274, with isonipecotamide substituted for piperidine. ES-MS:(M+H)⁺487.

Example 323

[1656]

[1657] The title compound was prepared using the same methodology shownfor Example 278, with isonipecotictamide substituted for piperidine.ES-MS: (M+H)⁺505.

Example 324

[1658]

[1659] The title compound was prepared using the same methodology shownfor Example 14, with azetidine substituted for pyrrolidine. ES-MS:(M+H)⁺428.

Example 325

[1660]

[1661] The title compound was prepared using the same methodology shownfor Example 23, with azetidine substituted for pyrrolidine. ES-MS:(M+H)⁺446.

Example 326

[1662]

[1663] The title compound was prepared using the same methodology shownfor Example 273, with azetidine substituted for pyrrolidine. ES-MS:(M+H)⁺416.

Example 327

[1664]

[1665] The title compound was prepared using the same methodology shownfor Example 277, with azetidinie substituted for pyrrolidine. ES-MS:(M+H)⁺434.

Example 328

[1666]

[1667] Step 1. Preparation of3-methyl-1-(3-fluoro-2-naphthyl)-5-amino-1H-pyrazole. It is described inStep 1, Example 166.

[1668] Step 2. To a solution of the above amine (200 mg, 0.82 mmol) in 5mL DMF were added tert-butyl4-(((methylsulfonyl)oxy)methyl)-1-piperidinecarboxylate (480 mg, 1.6mmol) and Cs₂CO₃ (0.53 g, 1.6 mmol). The mixture was stirred at 80° C.for overnight. The mixture was diluted with 200 mL EtOAc, washed withwater ×3, dried, concentrated in vacuuo. The residue was then dissolvedin dioxane (30 mL). To it was bubbled with HCl gas till saturation. Themixture was stirred for 5 hrs. It was concentrated and purified withprep HPLC to afford3-methyl-1-(3-fluoro-2-naphthyl)-5-((4-piperidinyl)methylamino)-1H-pyrazolein 40% yield. ES-MS: (M+H)⁺339.

[1669] Step 3. The above amine (50 mg, 0.15 mmol) was dissolved in 4 mLmethanol. To it were added acetic acid (0.2 mL), acetone (0.22 mL, 3mmol), NaBH₃CN (38 mg, 0.6 mmol). The mixture was stirred at 50° C. for6 hrs. The title compound was isolated with prep HPLC in 55% yield.ES-MS: (M+H)⁺381.

Example 329

[1670]

[1671] The title compound was prepared using the same methodologydescribed for Example 328, with cyclopentanone substituted for acetone.ES-MS: (M+H)⁺407.

Example 330

[1672]

[1673] The title compound was prepared using the same methodologydescribed for Example 328, with cyclohexanone substituted for acetone.ES-MS: (M+H)⁺421.

Example 331

[1674]

[1675] The title compound was prepared using the same methodologydescribed for Example 328, with 4-piperidone monohydrate hydrochloridesubstituted for acetone. ES-MS: (M+H)⁺422.

Example 332

[1676]

[1677] The title compound was prepared using the same methodologydescribed for Example 328, with tetrahydro-4H-pyran-4-one substitutedfor acetone. ES-MS: (M+H)⁺423.

Example 333

[1678]

[1679] Step 1. The mixture of 4-pyridineboronic acid (0.97 g, 7.8 mmol),4-piperidinemethanol (1.82 g, 15.8 mmol), Cu(OAc)₂ (2.88 g, 15.8 mmol),DMAP (catalytic amount), pyridine (2.5 mL, 32 mmol), 4A activatedmolecular sieve in 50 mL dry DCM was stirred for over 2 days. It wasdiluted with DCM, filtered through celite. It was washed with brine andwater, dried, filtered through a silica plug, evaporated in vacuuo togive 4-(4-hydroxylmethylpiperidin-1-yl)pyridine in 70% yield. ES-MS:(M+H)⁺193.

[1680] Step 2. The above alcohol (100 mg, 0.5 mmol) was dissolved in 4mL dry DCM. At 0° C. to it were added Et₃N (0.28 mL, 2.0 mmol) and themethanesulfonyl chloride (0.08 mL, 1.0 mmol, dropwise). After stirringfor 1 hr, the mixture was stirred for another 2 hrs at room temperature.The mixture was evaporated in vacuuo to afford the crude mesylate.

[1681] Step 3. The above mesylate was dissolved in 3 mL DMF. To it wereadded 3-methyl-1-(3-fluoro-2-naphthyl)-5-amino-1H-pyrazole (160 mg, 0.47mmol) and Cs₂CO₃ (300 mg, 0.92 mmol). The mixture was stirred forovernight at 50° C. The title compound was isolated using BPLC. ES-MS:(M+H)⁺416.

Example 334

[1682]

[1683] The title compound of Example 333 (12 mg, 0.03 mmol) wasdissolved in 3 mL acetone. To it was added MCPBA (11 mg, 0.04 mmol). Themixture was stirred for 5 hrs. The title compound was isolated usingKPLC. ES-MS: (M+H)⁺433.

Example 335

[1684]

[1685] Step 1. To the mixture of3-methyl-1-(3-fluoro-2-naphthyl)-5-amino-1H-pyrazole (200 mg, 0.48 mmol)and 4-bromomethylbenzonitrile (140 mg, 0.72 mmol) in 5 mL DMF was addedCS₂CO₃ (234 mg, 0.72 mmol). The mixture was stirred for overnight at 50°C. It was diluted with 200 mL EtOAc, washed with water ×2, dried,evaporated in vacuuo, purified using flash column to afford3-methyl-1-(3-fluoro-2-naphthyl)-5-((4-cyanophenyl)methylamino)-1H-pyrazole.ES-MS: (M+H)⁺357.

[1686] Step 2. The above-prepared nitrile (30 mg, 0.08 mmol) wasdissolved in 10 mL dry methanol. It was chilled and stirred in an icebath. To this solution was bubbled dry HCl gas via a long needle tillsaturation reached (indicated by a blown-up balloon attached on the topof the reaction flask). The resulting solution was stirred overnight.ES-MS (M+H)⁺389. The solvent was removed in vacuuo. The residue waspumped to dryness. The solid was dissolved in 5 mL dry methanol. To itwas added dimethylamine (2M in THF, 0.5 mL). The mixture was refluxedfor 1 hour, concentrated and loaded on prep HPLC to afford the titlecompound in 60% yield. ES-MS: (M+H)⁺402.

Example 336

[1687]

[1688] The title compound was prepared using the same methodologydescribed for Example 335, with pyrrolidine substituted fordimethylamine. ES-MS: (M+H)⁺428.

Example 337

[1689]

[1690] The title compound was prepared using the same methodologydescribed for Example 335, with piperidine substituted fordimethylamine. ES-MS: (M+H)⁺442.

Example 338

[1691]

[1692] The title compound was prepared using the same methodologydescribed for Example 335, with N-methylethylenediamine substituted fordimethylamine. ES-MS: (M+H)⁺414.

Example 339

[1693]

[1694] The title compound was prepared using the same methodologydescribed for Example 231, with 2-fluoro-4-methoxyaniline substitutedfor 3-fluoro-2-naphthylamine. ES-MS: (M+H)⁺456.

Example 340

[1695]

[1696] The title compound was prepared using the same methodologydescribed for Example 339, with pyrrolidine substituted fordirnethylamine. ES-MS: (M+H)⁺482.

Example 341

[1697]

[1698] The title compound was prepared using the same methodologydescribed for Example 339, with piperidine substituted fordimethylamine. ES-MS: (M+H)⁺496.

Example 342

[1699]

[1700] The title compound was prepared using the same methodologydescribed for Example 339, with isonipecotic acid substituted fordimethylamine. ES-MS: (M+H)⁺540.

Example 343

[1701]

[1702] The title compound was prepared using the same methodologydescribed for Example 339, with isonipecotamide substituted fordimethylamine. ES-MS: (M+H)⁺539.

Example 344

[1703]

[1704] The title compound was prepared using the same methodologydescribed for Example 339, with azetidin e substituted fordimethylamine. ES-MS: (M+H)⁺468.

Example 345

[1705]

[1706] The title compound was prepared using the same methodologydescribed for Example 339, with N-methylethylenediamine substituted fordimethylamine. ES-MS: (M+H)⁺468.

Example 346

[1707]

[1708] The title compound was prepared using the same methodologydescribed for Example 339, with 4-amino-3-fluorobenzonitrile substitutedfor 4-aminobenzotnile. ES-MS: (M+H)⁺474.

Example 347

[1709]

[1710] The title compound was prepared using the same methodologydescribed for Example 340, with 4-amino-3-fluorobenzonitrile substitutedfor 4-aminobenzotrile. ES-MS: (M+H)⁺500.

Example 348

[1711]

[1712] The title compound was prepared using the same methodologydescribed for Example 341, with 4-amino-3-fluorobenzonitrile substitutedfor 4-aminobenzotrile. ES-MS: (M+H)⁺514.

Example 349

[1713]

[1714] The title compound was prepared using the same methodologydescribed for Example 344, with 4-amino-3-fluorobenzonitrile substitutedfor 4-aminobenzotrile. ES-MS: (M+H)⁺486.

Example 350

[1715]

[1716] The title compound was prepared using the same methodologydescribed for Example 345, with 4-amino-3-fluorobenzonitrile substitutedfor 4-aminobenzotrile. ES-MS: (M+H)⁺486.

Example 351

[1717]

[1718] The title compound was prepared using the same methodologydescribed for Example 240, with 2-fluoro-4-methoxyaniline substitutedfor 3-fluoro-2-naphthylamine. ES-MS: (M+H)⁺457.

Example 352

[1719]

[1720] The title compound was prepared using the same methodologydescribed for Example 351, with pyrrolidine substituted fordimethylamine. ES-MS: (M+H)⁺483.

Example 353

[1721]

[1722] The title compound was prepared using the same methodologydescribed for Example 351, with piperidine substituted fordimethylamine. ES-MS: (M+H)⁺497.

Example 354

[1723]

[1724] The title compound was prepared using the same methodologydescribed for Example 351, with isonipecotic acid substituted fordimethylamine. ES-MS: (M+H)⁺541.

Example 355

[1725]

[1726] The title compound was prepared using the same methodologydescribed for Example 351, with isonipecotamide substituted fordimethylamine. ES-MS: (M+H)⁺540.

Example 356

[1727]

[1728] The title compound was prepared using the same methodologydescribed for Example 351, with azetidine substituted fordimethylaamine. ES-MS: (M+H)⁺469.

Example 357

[1729]

[1730] The title compound was prepared using the same methodologydescribed for Example 351, with N-methylethylenediamine substituted fordimethylamine. ES-MS: (M+H)⁺469.

Example 358

[1731]

[1732] The title compound was prepared using the same methodologydescribed for Example 351, with 4-amino-3-fluorobenzonitrile substitutedfor 4-aminobenzotrile. ES-MS: (M+H)⁺475.

Example 359

[1733]

[1734] The title compound was prepared using the same methodologydescribed for Example 352, with 4-amino-3-fluorobenzonitrile substitutedfor 4-aminobenzotrile. ES-MS: (M+H)⁺501.

Example 360

[1735]

[1736] The title compound was prepared using the same methodologydescribed for Example 353, with 4-amino-3-fluorobenzonitrile substitutedfor 4-aminobenzotrile. ES-MS: (M+H)⁺515.

Example 361

[1737]

[1738] The title compound was prepared using the same methodologydescribed for Example 356, with 4-amino-3-fluorobenzonitrile substitutedfor 4-aminobenzotrile. ES-MS: (M+H)⁺487.

Example 362

[1739]

[1740] The title compound was prepared using the same methodologydescribed for Example 357, with 4-amino-3-fluorobenzonitrile substitutedfor 4-aminobenzotrile. ES-MS: (M+H)⁺487.

[1741] BIOLOGICAL ACTIVITY EXAMPLES

[1742] Evaluation of the compounds of this invention is guided by invitro protease activity assays (see below) and in vivo studies toevaluate antithrombotic efficacy, and effects on hemostasis andhematological parameters.

[1743] The compounds of the present invention are dissolved in buffer togive solutions containing concentrations such that assay concentrationsrange from 0 to 100 μM. In the assays for thrombin, prothrombinase andfactor Xa, a synthetic chromogenic substrate is added to a solutioncontaining test compound and the enzyme of interest and the residualcatalytic activity of that enzyme is determined spectrophotometrically.The IC₅₀ of a compound is determined from the substrate turnover. TheIC₅₀ is the concentration of test compound giving 50% inhibition of thesubstrate turnover. The compounds of the present invention desirablyhave an IC₅₀ of less than 500 nM in the factor Xa assay, preferably lessthan 200 nM, and more prefeffed compounds have an IC₅₀ of about 100 nMor less in the factor Xa assay. The compounds of the present inventiondesirably have an IC₅₀ of less than 4.0 μM in the prothrombinase assay,preferably less than 200 nM, and more preferred compounds have an IC₅₀of about 10 nM or less in the prothrombinase assay. The compounds of thepresent invention desirably have an IC₅₀ of greater than 1.0 μM in thethrombin assay, preferably greater than 10.0 μM, and more preferredcompounds have an IC₅₀ of greater than 100.0 μM in the thrombin assay.

[1744] Amidolytic Assays for determining protease inhibition activity

[1745] The factor Xa and thrombin assays are performed at roomtemperature, in 0.02 M Tris·HCl buffer, pH 7.5, containing 0.15 M NaCl.The rates of hydrolysis of the para-nitroanilide substrate S-2765(Chromogenix) for factor Xa, and the substrate Chromozym TH (BoehringerMannheim) for thrombin following preincubation of the enzyme withinhibitor for 5 minutes at room temperature, and were determined usingthe Softmax 96-well plate reader (Molecular Devices), monitored at 405nm to measure the time dependent appearance of p-nitroaniline.

[1746] The prothrombinase inhibition assay is performed in a plasma freesystem with modifications to the method described by Sinha, U. et al.,Thromb. Res., 75, 427-436 (1994). Specifically, the activity of theprothrombinase complex is determined by measuring the time course ofthrombin generation using the p-nitroanilide substrate Chromozym TH. Theassay consists of preincubation (5 minutes) of selected compounds to betested as inhibitors with the complex formed from factor Xa (0.5 nM),factor Va (2 nM), phosphatidyl serine:phosphatidyl choline (25:75, 20μM) in 20 mM Tris·HCl buffer, pH 7.5, containing 0.15 M NaCl, 5 mM CaCl₂and 0.1% bovine serum albumin. Aliquots from the complex-inhibitormixture are added to prothrombin (1 nM) and Chromozym TH (0.1 mM). Therate of substrate cleavage is monitored at 405 nm for two minutes. Eightdifferent concentrations of inhibitor are assayed in duplicate. Astandard curve of thrombin generation by an equivalent amount ofuntreated complex are used for determination of percent inhibition.

[1747] Antithrombotic Efficacy in a Rabbit Model of Venous Thrombosis

[1748] A rabbit deep vein thrombosis model as described by Hollenbach,S. et al., Thromb. Haemost. 71, 357-362 (1994), is used to determine thein-vivo antithrombotic activity of the test compounds. Rabbits areanesthetized with I.M. injections of Ketamine, Xylazine, andAcepromazine cocktail. A standardized protocol consists of insertion ofa thrombogenic cotton thread and copper wire apparatus into theabdominal vena cava of the anesthetized rabbit. A non-occlusive thrombusis allowed to develop in the central venous circulation and inhibitionof thrombus growth is used as a measure of the antithrombotic activityof the studied compounds. Test agents or control saline are administeredthrough a marginal ear vein catheter. A femoral vein catheter is usedfor blood sampling prior to and during steady state infusion of testcompound. Initiation of thrombus formation begins immediately afteradvancement of the cotton thread apparatus into the central venouscirculation. Test compounds are administered from time=30 min totime=150 min at which the experiment is terminated. The rabbits areeuthanized and the thrombus excised by surgical dissection andcharacterized by weight and histology. Blood samples are analyzed forchanges in hematological and coagulation parameters.

[1749] Effects of Compounds in Rabbit Venous Thrombosis model

[1750] Administration of compounds in the rabbit venous thrombosis modeldemonstrates antithrombotic efficacy at the higher doses evaluated.There are no significant effects of the compound on the aPTT and PTprolongation with the highest dose (100 μg/kg+2.57 μg/kg/min). Compoundshave no significant effects on hematological parameters as compared tosaline controls. All measurements are an average of all samples aftersteady state administration of vehicle or (D)-Arg-Gly-Arg-thiazole.Values are expressed as mean ±SD.

[1751] Without further description, it is believed that one of ordinaryskill in the art can, using the preceding description and theillustrative examples, make and utilize the compounds of the presentinvention and practice the claimed methods. It should be understood thatthe foregoing discussion and examples merely present a detaileddescription of certain preferred embodiments. It will be apparent tothose of ordinary skill in the art that various modifications andequivalents can be made without departing from the spirit and scope ofthe invention. All the patents, journal articles and other documentsdiscussed or cited above are herein incorporated by reference.

What is claimed is:
 1. A compound of the formula (I): A-Q-D-E-G-J-Xwherein: A is selected from the group consisting of: —C₁₋₆alkyl and—C₃₋₈cycloalkyl; phenyl, which is substituted with 0-2 R¹ groups;naphthyl, which is substituted with 0-2 R¹ groups; and a 3-10 memberedaromatic or non-aromatic heterocyclic ring system which may be amonocyclic ring system or a fused bicyclic ring system, wherein theheterocyclic ring system contains 1-4 heteroatoms selected from N, O andS and is substituted with 0-2 R¹ groups; R¹ is independently selectedfrom the group consisting of: Halo, —CN, —C(═O)—N(R², R³), —NO₂,—SO₂N(R², R³), —SO₂R², —(CH₂)_(m)NR²R³, —(CH₂)_(m)—C(═NR³)—R²,—(CH₂)_(m)—C(═NR²)—N(R²,R³), —(CH₂)_(m)—N(R²)—C(═NR²)—N(R²,R³),—(CH₂)_(m)NR²—C₃₋₆heterocyclics, C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₃₋₈cycloalkyl, C₀₋₄alkylC₃₋₈cycloalkyl, —CF₃, —OR², and a 5-6 memberedheterocyclic system containing from 1-4 heteroatoms selected from N, Oand S, wherein from 1-4 hydrogen atoms on the heterocyclic system may beindependently replaced with a member selected from the group consistingof halo, C₁-C₄-alkyl, —CN, C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₃₋₈cycloalkyl, C₀₋₄alkylC₃₋₈cycloalkyl and —NO₂; R² and R³ areindependently selected from the group consisting of: —H, —C₁₋₆alkyl,—C₁₋₆alkyloxy, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,—C₀₋₆alkylC₃₋₈cycloalkyl and —C₀₋₆alkyl-(carbocyclic aryl), wherein from0-4 hydrogen atoms on the ring atoms of the carbocyclic aryl moiety maybe independently replaced with a member selected from the groupconsisting of halo, —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,—C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl, —S(═O)₂—OH, —CN, —CF₃ and—NO₂; m is an integer of 0-2; Q is selected from the group consistingof: a direct link, divalent —C₁₋₄alkyl, divalent —C₂₋₄alkenyl, divalent—C₂₋₄alkynyl, —C(═O)—, —C(═NH)—, —C(═NMe)—, —NH—C(—NH)—, —NH—C(═NMe)—,—N(—R⁴)—, —N(—R⁴)—CH₂—, —C(═O)—N(—R⁴)—, —N(—R⁴)—C(═O)—, —S(═O)₂—, —O—,—S(═O)₂—N(—R⁴)— and —N(—R⁴)—S(═O)₂—, wherein one or more hydrogens oneach of the divalent C₁₋₄alkyl, divalent C₂₋₄alkenyl and divalentC₂₋₄alkynyl moieties can be replaced with a —R⁴ group; R⁴ is selectedfrom the group consisting of: —H, —C₁₋₆alkyl, —C₁₋₆alkyloxy,—C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl, —C₀₋₆alkylC₃₋₈cycloalkyland —C₀₋₆alkyl-(carbocyclic aryl), wherein from 0-4 hydrogen atoms onthe ring atoms of the carbocyclic aryl moiety may be independentlyreplaced with a member selected from the group consisting of halo,—C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,—C₀₋₄alkylC₃₋₈cycloalkyl, —S(═O)₂—OH, —CN, —CF₃ and —NO₂; D is selectedfrom the group consisting of: a direct link; phenyl, which issubstituted with 0-2 R^(1a) groups; and a 5-10 membered aromatic ornon-aromatic heterocyclic ring system which may be a monocyclic ringsystem or a fused bicyclic ring system, wherein the heterocyclic ringsystem contains 1-4 heteroatoms selected from N, O and S and the ringsystem is substituted with 0-2 R^(1a) groups; R^(1a) is independentlyselected from the group consisting of: halo, —C₁₋₆alkyl, —C₁₋₆alkyloxy,—C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl, —C₀₋₆alkylC₃₋₈cycloalkyl,—S (═O)₂—OH, —CN, —NO₂, (CH₂)_(n)—N(R^(2a), R^(3a)), S(═O)₂—N(—R^(2a),—R^(3a)) S(═O)₂R^(2a), —CF₃, (CH₂)_(n)—OR^(2a), C(═O)—O—R^(2a),—C(═O)—N(—R^(2a), —R^(3a)), —C(═NH)—N(—R^(2a), —R^(3a)),—C(═NMe)—N(R^(2a), —R^(3a)), 2-imidazolin-2-yl,1-methyl-2-imidazolin-2-yl and a 5-6 membered aromatic heterocyclic ringcontaining 1-4 heteroatoms selected from N, O and S and—C₀₋₆alkyl-(carbocyclic aryl), wherein from 0-4 hydrogen atoms on thering atoms of the aromatic heterocyclic ring and the carbocyclic arylmoiety may be independently replaced with a member selected from thegroup consisting of halo, —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,—C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl, —CN, —CF₃ and —NO₂; n is aninteger of 0-2; R^(2a) and R^(3a) are independently selected from thegroup consisting of: —H, —C₁₋₆alkyl, —C₁₋₆alkyloxy, —C₂₋₆alkenyl,—C₂₋₆alkynyl, —C₃₋₈cycloalkyl, —C₀₋₆alkylC₃₋₈cycloalkyl and—C₀₋₆alkyl-(carbocyclic aryl), wherein from 0-4 hydrogen atoms on thering atoms of the carbocyclic aryl moiety may be independently replacedwith a member selected from the group consisting of halo, —C₁₋₄alkyl,—C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl,—S(═O)₂—OH, —CN, —CF₃ and —NO₂; E is selected from the group consistingof: a direct link, —(CH₂)_(q)—C(═O), —(CH₂)_(q)—N(R⁵)—C(═O)—(CH₂)_(x)—,—(CH₂)_(q)—C(═O)—N(—R⁵)—(CH₂)_(x)—, —(CH₂)_(q)—N(—R⁵)—(CH₂)_(x)—,—(CH₂)_(q)—N(R⁵)CO—NR⁶(CH₂)_(x) and —SO₂—; q and x are independently aninteger of 0-2; R⁵ and R⁶ are independently selected from the groupconsisting of: —H, —C₁₋₆alkyl, —C₁₋₆alkyloxy, —C₂₋₆alkenyl,—C₂₋₆alkynyl, —C₃₋₈cycloalkyl, —C₀₋₆alkylC₃₋₈cycloalkyl,—C₁₋₄alkyl—C(═O)—OH, —C₀₋₆alkyl-(carbocyclic aryl),—C₀₋₄alkyl-(monocyclic heteroaryl) and —C₁₋₄alkyl—C(═O)—O—C₁₋₄alkyl,wherein from 0-4 hydrogen atoms on the ring atoms of the carbocyclicaryl moiety and the monocyclic heteroaryl moieties may be independentlyreplaced with a member selected from the group consisting of halo,—C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆atkynyl, —C₃₋₈cycloalkyl,—C₀₋₄alkylC₃₋₈cycloalkyl, —S(═O)₂—OH, —CN, —CF₃ and —NO₂; G is selectedfrom the group consisting of: phenyl, which is substituted with 0-2R^(1b) groups; and a 5-6 membered aromatic heterocyclic ring containing1-4 hetero atoms selected from N, O and S wherein the heterocyclic ringis substituted with 0-2 R^(1b) groups; R^(1b) is independently selectedfrom the group consisting of: halo, —C₁₋₆alkyl, —C₂₋₆alkenyl,—C₂₋₆alkynyl, —C₃₋₈cycloalkyl, —C₀₋₆alkylC₃₋₈cycloalkyl,—C₁₋₄alkyl—C(═O)—OH, —CN, —NO₂, —S(═O)₂—OH, —N(—R^(2b) , —R^(3b) ),—C(═O)—N(—R^(2b), —R^(3b)), —S(═O)₂—N(—R^(2b), —R^(3b)), —S(═O)₂—R^(2b),—CF₃, —O—R^(2b), —O—CH₂—CH₂—O—R^(2b), —O—CH₂—C(═O)—O—R^(2b),—N(—R^(2b))—CH₂—CH₂—O—R^(2b), —N(—CH₂—CH₂—O—R^(2b))₂,—N(—R^(2b))—C(═O)—R^(3b), —N(—R^(2b))—S(═O)—R^(3b), and a 5-6 memberedheterocyclic ring containing 1-4 heteroatoms selected from N, O and Ssubstituted with 0-4 R^(1b) groups; alternatively, when two R^(1b) maybe present on adjacent ring atoms of G and combine to form a benzenering substituted with 0-4 R^(1b′) groups or a 5-6 membered aromatic ornon-aromatic heterocyclic ring having 1-3 heteroatoms selected from N, Oand S substituted with 0-4 R^(1b′) groups; in a second alternative, oneof the R^(1b) groups of G can cylize with the —N—R⁵ group of E to form a5-7 membered heterocyclic ring containing 1-4 heteroatoms selected fromN, O and S, which is subtituted with 0-4 R^(1b′) groups, wherein two ofthe R^(1b′) groups attached to the same ring carbon may form a (═O)group; R^(2b) and R^(3b) are independently selected from the groupconsisting of: —H, —C₁₋₆alkyl, —C₁₋₆alkyloxy, —C₂₋₆alkenyl,—C₂₋₆alkynyl, —C₃₋₈cycloalkyl, —C₀₋₆alkylC₃₋₈cycloalkyl and—C₀₋₆alkyl-(carbocyclic aryl), wherein from 0-4 hydrogen atoms on thering atoms of the carbocyclic aryl moiety may be independently replacedwith a member selected from the group consisting of halo, —C₁₋₄alkyl,—C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl,—S(═O)₂—O, —CN, —CF₃ and —NO₂; R^(1b′) is independently selected fromthe group consisting of: halo, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,—C₃₋₈cycloalkyl, —C₀₋₆alkylC₃₋₈cycloalkyl, —C₁₋₄alkyl—C(═O)—OH, —CN,—NO₂, —S (═O)₂—OH, —N(—R^(2b′), —R^(3b′)), —C(═O)—N(—R^(2b′), R^(3b′)),—S(═O)₂—N(R^(2b′), —CF₃, —O—R^(2b′), —O—CH₂—CH₂—O—R^(2b′),—O—CH₂—C(═O)—O—R^(2b′), —N—(R^(2b′))—CH₂—CH₂—O—R^(2b′),—N(—CH₂—CH₂—O—R^(2b′))₂, —N(—R^(2b′))—C(═O)—R^(3b′) and—N(—R^(2b′))—S(═O)₂—R^(3b′); R^(2b′) 0 and R^(3b′) are independentlyselected from the group consisting of: —H, —C₁₋₆alkyl, —C₁₋₆alkoxy,—C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl, —C₀₋₆alkylC₃₋₈cycloalkyland —C₀₋₆alkyl-(carbocyclic aryl), wherein from 0-4 hydrogen atoms onthe ring atoms of the carbocyclic aryl moiety may be independentlyreplaced with a member selected from the group consisting of halo,—C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloakyl,—C₀₋₄alkylC₃₋₈cycloalkyl, —S(═O)₂—OH, —CN, —CF₃ and —NO₂; J is selectedfrom the group consisting of: a direct link, —S(═O)₂—, —C(═O)—,—N(—R⁷)—S(═O)₂—, —C(═O)—N(—R⁷)—S(═O)₂—, —C(═O)—N(—R⁷)—(CH₂)_(y)—,—S(═O)₂—N(—R⁷)—(CH₂)_(y)—, and —N(—R⁷)—C(═O)—(CH₂)_(y)—; y is an integerof 0-2; R⁷ is selected from the group consisting of: —H, —C₂₋₄alkyl,—C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl, —C₀₋₆alkylC₃₋₈cycloalkyl,—C₁₋₆alkyl—C(═O)—OH, —C₁₋₆alkyl—OH, —C₁₋₆alkyl-O—C₁₋₄alkyl,—C₀₋₄alkyl-(carbocyclic aryl), —C₀₋₄alkyl-(monocyclic or bicyclicheterocyclic ring system having from 0-4 heteroatoms selected from thegroup consisting of N, O and S), —CH₂—C(═O)—O—C₁₋₄alkyl and—CH₂—C(═O)—O—C₁₋₄alkyl-(carbocyclic aryl), wherein from 0-4 hydrogenatoms on the ring atoms of the carbocyclic aryl moiety or theheterocyclic ring system may be independently replaced with a memberselected from the group consisting of halo, —C₁₋₄alkyl, —C₂₋₆alkenyl,—C₂₋₆alkynyl, —C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl, —S(═O)₂—OH,—CN, —CF₃ and —NO₂; X is a member selected from the group consisting of:phenyl, which is substituted with 0-3 R^(1c) groups; naphthyl, which issubstituted with 0-3 R^(1c) groups; a 6-membered heteroaromatic ringcontaining from 1-2 nitrogen atoms, wherein the ring is substituted with0-3 R^(1c) groups; and a fused heterobicyclic ring system, wherein thering system contains 1-3 heteroatoms selected from N, O and S and issubstituted with 0-3 R^(1c) groups; R^(1c) is independently selectedfrom the group consisting of: halo, —CF₃, —C₁₋₆alkyl, —C₂₋₆alkenyl,—C₂₋₆alkynyl, —C₃₋₈cycloalkyl, —C₀₋₆alkylC₃₋₈cycloalkyl,—C₁₋₄alkyl—C(═O)—OH, —CF₃, —CN, —NO₂, —(CH₂)_(z)—N(—R^(2c), —R^(3c)),—C(═O)—N(—R^(2c), —R^(3c)), —C(═NH)—N(—R^(2c), —R^(3c)),—C(═NMe)—N(—R^(2c), —R^(3c)), —S(═O)₂—N(—R^(2c), —R^(3c)),—S(═O)₂—R^(2c), —S(═O)₂—OH, —CF₃, —O—R^(2c), —O(—CH₂)_(z)—O—R^(2c),—O(—CH₂ )—C(═O)—O—R^(2c), —N(—R^(2c)), —O(—CH₂)_(z)—O—R^(2c),—N[(—CH₂)_(z)—O—R^(2c)]₂, —(CH₂)_(z)—N(—R^(2c))—C(═O)—R^(3c),—(CH₂)_(z)—N(—R^(2c))—S(═O)₂—R^(3c), and a 5-6 membered heterocyclicring containing 1-4 heteroatoms selected from N, O and S; z is aninteger of 0-4; R^(2c) and R^(3c) are independently selected from thegroup consisting of: —H, —C₁₋₆alkyl, —C₁₋₆alkyloxy, —C₂₋₆alkenyl,—C₂₋₆alkynyl, —C₃₋₈cycloalkyl, —C₀₋₆alkylC₃₋₈cycloalkyl and—C₀₋₆alkyl-(carbocyclic aryl), wherein from 0-4 hydrogen atoms on thering atoms of the carbocyclic aryl moiety may be independently replacedwith a member selected from the group consisting of halo, —C₁₋₄alkyl,—C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl,—S(═O)₂—OH, —CN, —CF₃ and —NO₂; and all pharmaceutically acceptableisomers, salts, hydrates, solvates and prodrug derivatives thereof.
 2. Acompound of claim 1, wherein: A is selected from the group consistingof: —C₁₋₆alkyl and —C₃₋₈cycloalkyl; phenyl, which is substituted with0-2 R¹ groups; naphthyl, which is substituted with 0-2 R¹ groups; and a3-10 membered aromatic or non-aromatic heterocyclic ring system whichmay be a monocyclic ring system or a fused bicyclic ring system, whereinthe heterocyclic ring system contains 1-4 heteroatoms selected from N, Oand S and is substituted with 0-2 R¹ groups; R¹ is independentlyselected from the group consisting of: halo, —C₁₋₄alkyl, —CN, —NO₂,—(CH₂)_(m)—N(—R²,—R³), —C(═O)—N(—R²,—R³), —S(═O)₂—N(—R²,—R³),—S(═O)₂—R², —(CH₂)_(m)—C(═NR³)—R², —(CH₂)_(m)—C(═NR²)—N(R²,R³),—(CH₂)_(m)—N(R²)—C(═NR²)—N(R², R³), —CF₃, —(CH₂)_(m)—O—R² and a 5-6membered aromatic heterocyclic ring containing 1-4 heteroatoms selectedfrom N, O and S; R² and R³ are independently selected from the groupconsisting of: —H, —C₁₋₄alkyl and —C₀₋₄alkyl-(carbocyclic aryl); m is aninteger of 0-2; Q is selected from the group consisting of: a directlink, —C₁₋₄alkyl, —C₂₋₄alkenyl, —C₂₋₄alkynyl, —C(═O)—, —C(═NH)—,—C(═NMe)—, —N(—R⁴)—, —N(—R⁴)—CH₂—, —C(═O)—N(—R⁴)—, —N(—R⁴)—C(═O)—,—S(═O)₂—, —O—, —S(═O)₂—N(—R⁴)— and —N(—R⁴)—S(═O)₂—; R⁴ is selected fromthe group consisting of: —H, —C₁₋₄alkyl and —C₀₋₄alkyl-(carbocyclicaryl); D is selected from the group consisting of: a direct link;phenyl, which is substituted with 0-2 R^(1a) groups; and a 5-10 memberedaromatic or non-aromatic heterocyclic ring system which may be amonocyclic ring system or a fused bicyclic ring system, wherein theheterocyclic ring system contains 1-4 heteroatoms selected from N, O andS and the ring system is substituted with 0-2 R^(1a) groups; R^(1a) isindependently selected from the group consisting of: halo, —C₁₋₄alkyl,—CN, —NO₂, —(CH₂)_(n), —N(—R^(2a), —R^(3a)), —S(═O)₂—N(—R^(2a),—R^(3a)), —S(═O)₂—R^(2a), —CF₃, —(CH₂)_(n)—OR^(2a), —C(═O)—O—R^(2a),—C(═O)—N(—R^(2a), —R^(3a)) and a 5-6 membered aromatic heterocyclic ringcontaining 1-4 heteroatoms selected from N, O and S; n is an integer of0-2; R^(2a) and R^(3a) are independently selected from the groupconsisting of: —H, —C₁₋₄alkyl, and —C₁₋₄alkyl-(carbocyclic aryl); E isselected from the group consisting of: a direct link, —(CH₂)_(q)—C(═O)—,—(CH₂)_(q)—N(—R⁵)—C(═O)—(CH₂)_(x)—, —(CH₂)_(q)—C(═O)—N(—R⁵)—(CH₂)_(x)—,—(CH₂)_(q)—N(—R⁵)—(CH₂)_(x)—, —(CH₂)_(q)—N(R⁵)CO—NR⁶(CH₂)_(x)— and—SO₂—; q and x are independently an integer of 0-2; R⁵ and R⁶ areindependently selected from the group consisting of: —H, —C₁₋₄alkyl,—C₀₋₄alkyl-(carbocyclic aryl), —C₀₋₄alkyl-(monocyclic heteroaryl),—C₁₋₄alkyl—C(═O)—OH and —C₁₋₄alkyl—C(═O)—O—C₁₋₄alkyl; G is selected fromthe group consisting of: phenyl, which is substituted with 0-2 R^(1b)groups; and a 5-6 membered aromatic heterocyclic ring containing 1-4hetero atoms selected from O, S and N, wherein the heterocyclic ring issubstituted with 0-2 R^(1b) groups; R^(1b) is independently selectedfrom the group consisting of: halo, —C₁₋₄alkyl, —CN, —NO₂, —N(—R^(2b),—R^(3b)), —C(═O)—N(—R^(2b), —R^(3b)), —S(═O)₂—N(—R^(2b), —R^(3b)),—S(═O)₂R^(2b), —CF₃, —O—R^(2b), —O—CH₂—CH₂—O—R^(2b),—O—CH₂—C(═O)—O—R^(2b), —N(—R^(2b))—CH₂—CH₂—O—R^(2b),—N(—CH₂—CH₂—O—R^(2b))₂, —N(—R^(2b))—C(═O)—R^(3b),—N(—R^(2b))—S(═O)₂—R^(3b) and a 5-6 membered heterocyclic ringcontaining 1-4 heteroatoms selected from N, O and S; alternatively, whentwo R^(1b) may be present on adjacent ring atoms of G and combine toform a benzene ring substituted with 0-4 R^(1b′) groups or a 5-6membered aromatic or non-aromatic heterocyclic ring having 1-3heteroatoms selected from N, O and S substituted with 0-4 R^(1b′)groups; in a second alternative, one of the R^(1b) groups of G cancylize with the —N—R⁵ group of E to form a 5-7 membered saturated,unsaturated or partially unsaturated heterocyclic ring containing 1-4heteroatoms selected from N, O and S, which is substituted with 0-4R^(1b′) groups, wherein two of the R^(1b′) groups attached to the samering carbon may form a (═O) group; R^(2b) and R^(3b) are independentlyselected from the group consisting of: —H, —C₁₋₄alkyl and—C₁₋₄alkyl-(carbocyclic aryl); R^(1b′) is independently selected fromthe group consisting of: halo, —C₁₋₄alkyl, —CN, —NO₂, —N(—R^(2b′),—R^(3b′)), —C(═O)—N(—R^(2b′), —R^(3b′)), —S(═O)₂—N(—R^(2b′), —R^(3b′)),—S(═O)₂—R^(2b′), —CF₃, —O—R^(2b′), —O—CH₂—C(═O)—O—R^(2b′),—N(—R^(2b′))—CH₂—CH₂—O—R^(2b′), —N(—CH₂—CH₂—O—R^(2b′))₂,—N(—R^(2b′))—C(═O)—R^(3b′), —N(—R^(2b′)) —S(═O)₂R^(3b′); R^(2b′) andR^(3b′) are independently selected from the group consisting of: —H,—C₁₋₄alkyl and —C₁₋₄alkyl-(carbocyclic aryl); J is selected from thegroup consisting of: a direct link, —S(═O)₂—, —C(═O)—, —N(—R⁷)—S(═O)₂—,—C(═O)—N(—R⁷)—S(═O)₂—, —C(═O)—N(—R⁷)—(CH₂)_(y)—, —S(═O)₂—N(—R⁷)—,—(CH₂)_(y)— and —N(—R⁷)—C(═O)—(CH₂)_(y)—; y is an integer of 0-2; R⁷ isselected from the group consisting of: —H, —C₁₋₄alkyl, —C₂₋₆alkenyl,—C₂₋₆alkynyl, —C₀₋₄alkyl-(carbocyclic aryl), —C₀₋₄alkyl-(heterocyclicring system), —CH₂—C(═O)—O—C₁₋₄alkyl and—CH₂—C(═O)—O—C₁₋₄alkyl-(carbocyclic aryl); X is selected from the groupconsisting of: phenyl, which is substituted with 0-3 R^(1c) groups;naphthyl, which is substituted with 0-3 R^(1c) groups; a 6-memberedheteroaromatic ring containing from 1-2 nitrogen atoms, wherein the ringis substituted with 0-3 R^(1c) groups; and a fused heterobicyclic ringsystem, wherein the ring system contains 1-3 heteroatoms selected fromN, O and S and is substituted with 0-3 R^(1c) groups; R^(1c) isindependently selected from the group consisting of: halo, —C₁₋₄alkyl,—CN, —NO₂, —(CH₂)_(z)—N(—R^(2c), —R^(3c)), —C(═O)—N(—R^(2c), —R^(3c)),—C(═NH)—N(—R^(2c), —R^(3c)), —C(═NMe)—N(—R^(2c), —R^(3c)),—S(═O)₂—N(—R^(2c), —R^(3c)), —S(═O)₂—R^(2c), —S(═O)₂—O—, —CF₃,—O—R^(2c)—)—CH₂—CH₂—O—R^(2c),—O—CH₂—C(═O)—O—R^(2c)—N(—R^(2c))CH₂—CH₂—O—R^(2c),—N(—CH₂—CH₂—O—R^(2c))₂, —(CH₂)_(z)—N(—R^(2c))—C(═O)—R^(3c),—(CH₂)_(z)—N(—R^(2c))—S(═O)₂—R^(3c), and a 5-6 membered heterocyclicring containing 1-4 heteroatoms selected from N, O and S; z is aninteger of 0-2; R^(2c) and R^(3c) are independently selected from thegroup consisting of: —H, —C₁₋₄alkyl and —C₁₋₄alkyl-(carbocyclic aryl);and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives, thereof.
 3. A compound of claim 1, wherein: Ais selected from the group consisting of:

Q is selected from the group consisting of: a direct link, —C(═NH),—C(═NMe)—, —C(═O)—, —CH₂—, —NH—, —N(—CH₃)—, —O—, —NH—CH₂—, —CH₂—NH—,—N(—CH₃)—CH₂—, and —CH₂—N(—CH₃)—; D is selected from the groupconsisting of:

E is selected from the group consisting of: a direct link, —NH—C(═O)—,—N(—CH₃)—C(═O)—, —N(—CH₂CO₂H)—C(═O)—, —C(═O)—NH—, —C(═O)—N(—CH₃)—,—NH—CH₂— and —CH₂—NH—; G is a member selected from the group consistingof:

R^(1b) is selected from the group consisting of: —H, —Me, —CF₃, —F, —Cl,—Br, —SO₂Me, —CN, —CONH₂, —CONMe₂, —NH₂, —NO₂, —NHCOMe, —NHSO₂Me,—CH₂NH₂ and —CO₂H; J is selected from the group consisting of: a directlink, —NH—, —O—, —S(═O)₂—, —S(═O)₂—NH, —NH—S(═O)₂—, —C(═O)—, —NH—C(═O)—and —C(═O)—NH—; X is selected from the group consisting

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives, thereof.
 4. A compound of claim 1, wherein: Ais selected from the group consisting of: phenyl, which is substitutedwith 0-2 R¹ groups; naphthyl, which is substituted with 1 R¹ group; anda 5-7 membered aromatic or non-aromatic monocyclic heterocyclic ring,wherein the hetero cyclic ring contains 1-2 hetero atoms selected fromN, O and S and is substituted with 0-1 R¹ groups; R¹ is selected fromthe group consisting of: —S(═O)₂—N(—R², —R³), —S(═O)₂—R², —CH₂N(—R²,—R³), —CN and halo. R² and R³ are independently selected from the groupconsisting of: —H and —C₁₋₄alkyl; Q is selected from the groupconsisting of: a direct link, —C(═NH), —C(═NMe)—, —C(═O)—, —CH₂—, —NH—,and —N(—CH₃)—; D is selected from the group consisting of: a directlink; phenyl, which is substituted with 0-2 R^(1a) groups; and a 5-6membered aromatic heterocyclic ring, wherein the heterocyclic ringcontains 1-2 heteroatoms selected from N and S and is substituted with0-1 R^(1a) groups; R^(1a) is selected from the group consisting of: —Hand halo; E is selected from the group consisting of: a direct link,—NH—C(═O)— and —C(═O)—NH—; G is selected from the group consisting of:Pyrazole, pyrazoline, triazole and tertrazole, which are substitutedwith 0-2 R^(1b) groups; and a 5-membered aromatic heterocyclic ring,wherein the heterocyclic ring contains 2 heteroatoms selected from N, Oand S and is substituted with 0-1 R^(1b) groups and; R^(1b) is selectedfrom the group consisting of: —Me, —Et, —CF₃, —C(═O)—NH₂, —NH₂,—NH—C(═O)—Me, —NH—S(═O)₂—Me, —SMe, —S(═O)₂—Me and halo; alternatively,when two R^(1b) groups may be present on adjacent ring atoms of G andcombine to form a benzene ring; in a second alternative, one of theR^(1b) groups of G can cyclize with the NH group of E to form a 5-6membered non-aromatic heterocyclic ring containing 1-2 nitrogen atomsand which is substituted with 0-2 C═O groups; J is selected from thegroup consisting of: a direct link, —NH—C(═O)— and —C(═O)—NH—; X isselected from the group consisting of: phenyl, which is substituted with1-3 R^(1c) groups; naphthyl, which is substituted with 0-3 R^(1c)groups; pyridinyl, which is substituted with 1-3 R^(1c) groups; and a9-10 membered fused bicyclic aromatic ring, wherein the aromatic ringcontains 0-2 heteroatoms selected from N and O and is substituted with0-3 R^(1c) groups; R^(1c) is independently selected from the groupconsisting of: —H, halo, —Me, —CF₃, —OH, —OMe, —NH₂, —CN, —NO₂,—CH₂—R^(2c), —C(═O)—N(—R^(2c), —R^(3c)), —S(═O)₂—R^(2c),—S(═O)₂—N(—R^(2c), —R^(3c)), —S(═O)₂—OH, —C(═NH)—N(—R^(2c), —R^(3c)),2-imidazolin-2-yl and 1-methyl-2-imidazolin-2-yl; R^(2c) and R^(3c) areindependently selected from the group consisting of: —H, —OH, —NH₂ and—Cl₄alkyl, and all pharmaceutically acceptable isomers, salts, hydrates,solvates and prodrug derivatives, thereof.
 5. The following compoundsare claimed by the present invention:

wherein: R¹ is selected from the group consisting of: —SO₂NH₂, —SO₂Me,—CH₂NH₂ and —CH₂NMe₂; R^(1a) is selected from the group consisting of:—H, —F, —Cl and —Br; R^(1c1) is selected from the group consisting of:—H, —F, —Cl, —Br, —NH₂, —OH, —SO₂Me, —SO₂Et, —SO₂NH₂, —NO₂, —CH₂NH₂,—CN, —CONH₂, —CH₂OH; R^(1c2) is selected from the group consisting of:—H, —F, —Cl and —Br; R^(1c3) is selected from the group consisting of:—H, —F, —Cl and —Br; G is selected from the group consisting of:

wherein: R^(1b1) is selected from the group consisting of —H, —CH₃ and—CF₃; R^(1b2) is selected from the group consisting of —H, —CH₃ and—CF₃; R^(1b3) is selected from the group consisting of —Cl, —NH₂, —CH₃and —CF₃.
 6. The following compounds are claimed by the presentinvention:

wherein: R¹ is selected from the group consisting of: —SO₂NH₂, —SO₂Me,—CH₂NH₂ and —CH₂NMe₂; R^(1a) is selected from the group consisting of:—H, —F, —Cl and —Br; R^(1c1) is selected from the group consisting of:—H, —F, —Cl, —Br, —NH₂, —OH, —SO₂Me, —SO₂Et, —SO₂NH₂, —NO₂, —CH₂NH₂,—CN, —CONH₂, —CH₂OH; R^(1c2) is selected from the group consisting of:—H, —F, —Cl, —Br and —OMe; R^(1c3) is selected from the group consistingof: —H, —F, —Cl, —Br, —OCH₃, —NH₂, —CH₂NH₂, —CONH₂, —CONHMe, —CONMe₂ Gis selected from the group consisting of:

wherein: R^(1b1) is selected from the group consisting of —H, —CH₃ and—CF₃; R^(1b2) is selected from the group consisting of —H, —CH₃ and—CF₃; R^(1b3) is selected from the group consisting of —Cl, —NH₂, —CH₃and —CF₃.
 7. The following compounds are claimed by the presentinvention:

wherein: R¹ is selected from the group consisting of: —SO₂NH₂, —SO₂CH₃,—CN, —CONH₂, —CONH(CH₃), —CON(CH₃)₂ —CH₂NH₂, —CH₂NH(CH₃)₂—CH₂N(CH₃)₂;R^(1a) is selected from the group consisting of: —H, —F, —Cl and —Br;R^(1c1) is selected from the group consisting of: —H, —F, —Cl, —Br, —CN,—CH₂NH₂, —CH₂OH, —CONH₂, —C(═NH)NH₂, —CO₂H, —CO₂Me, —SO₂Me, —SO₂NH₂,—OH, —NH₂, and —NO₂; R^(1c2) is selected from the group consisting of:—H, —F, —Cl, —Br, and —OCH₃; R^(1c3) is selected from the groupconsisting of: —H, —F, —Cl, —Br, —OCH₃, —NH₂, —CH₂NH₂, —CONH₂, —CONHMe,—CONMe₂; G is selected from the group consisting of:

wherein: R^(1b1) is selected from the group consisting of —H, —CH₃ and—CF₃; R^(1b2) is selected from the group consisting of —H, —CH₃ and—CF₃; R^(1b3) is selected from the group consisting of —Cl, —NH₂, —CH₃and —CF₃.
 8. The following compounds are claimed by the presentinvention:

wherein: R¹ is selected from the group consisting of: —SO₂NH₂, —SO₂Me,—CH₂NH₂ and —CH₂NMe₂; R^(1a) is selected from the group consisting of:—H, —F, —Cl and —Br; R^(1c) is selected from the group consisting of:—H, —F, —Cl, —Br, —NH₂, —OH, —SO₂Me, —SO₂Et, —SO₂NH₂, —NO₂, —CH₂NH₂,—CN, —CONH₂, —CH₂OH; G is selected from the group consisting of:

wherein: R^(1b1) is selected from the group consisting of —H, —CH₃ and—CF₃; R^(1b2) is selected from the group consisting of —H, —CH₃ and—CF₃; R^(1b3) is selected from the group consisting of —Cl, —NH₂, —CH₃and —CF₃.
 9. The following compounds are claimed by the presentinvention:

wherein: R¹ is selected from the group consisting of: —SO₂NH₂, —SO₂Me,—CH₂NH₂ and —CH₂NMe₂; R^(1a) is selected from the group consisting of:—H, —F, —Cl and —Br; R^(1c1) is selected from the group consisting of:—H, —F, —Cl, —Br, —NH₂, —OH, —SO₂Me, —SO₂Et, —SO₂NH₂, —NO₂, —CH₂NH₂,—CN, —CONH₂, —CH₂OH; R^(1c2) is selected from the group consisting of:—H, —F, —Cl and —Br; G is selected from the group consisting of:

wherein: R^(1b1) is selected from the group consisting of —H, —CH₃ and—CF₃; R^(1b2) is selected from the group consisting of —H, —CH₃ and—CF₃; R^(1b3) is selected from the group consisting of —Cl, —NH₂, —CH₃and —CF₃.
 10. The following compounds are claimed by the presentinvention:

wherein: A-Q is selected from the group consisting of:

wherein: A is selected from the group consisting of:

R^(1a) is selected from the group consisting of —H, —F, —Cl and —Br;R^(1c1) is selected from the group consisting of: —H, —F, —Cl, —Br,—NH₂, —OH, —SO₂Me, —SO₂Et, —SO₂NH₂, —NO₂, —CH₂NH₂, —CN, —CONH₂, —CH₂OH;R^(1c2) is selected from the group consisting of: —H, —F, —Cl and —Br;R^(1c3) is selected from the group consisting of: —H, —F, —Cl and —Br; Gis selected from the group consisting of:

wherein: R^(1b1) is selected from the group consisting of —H, —CH₃ and—CF₃; R^(1b2) is selected from the group consisting of —H, —CH₃ and—CF₃; R^(1b3) is selected from the group consisting of —Cl, —NH₂, —CH₃and —CF₃.
 11. The following compounds are claimed by the presentinvention:

wherein: A-Q is selected from the group consisting of:

wherein: A is selected from the group consisting of:

R^(1a) is selected from the group consisting of: —H, —F, —Cl and —Br;R^(1b) is selected from the group consisting of: —CH₃, —CF₃, —CH₂CH₃,—SO₂Me, —CONH₂ and —NHSO₂Me; R^(1c2) is selected from the groupconsisting of: —H, —F, —Cl, —Br, —NH₂, —OH, —SO₂Me, —SO₂Et, —SO₂NH₂,—NO₂, —CH₂NH₂, —CN, —CONH₂, —CH₂OH; R^(1c2) is selected from the groupconsisting of: —H, —F, —Cl, —Br and —OMe; R^(1c3) is selected from thegroup consisting of: —H, —F, —Cl, —Br, —OH, —OCH₃, —NH₂, —CONH₂,—CH₂NH₂; G is selected from the group consisting of:

wherein: R^(1b1) is selected from the group consisting of —H, —CH₃ and—CF₃; R^(1b2) is selected from the group consisting of —H, —CH₃ and—CF₃; R^(1b3) is selected from the group consisting of —Cl, —NH₂, —CH₃and —CF₃.
 12. The following compounds are c laimed by the presentinvention:

wherein: R¹ is selected from the group consisting of: —SO₂NH₂, —SO₂CH₃,—CN, —CONH₂, —CONH(CH₃), —CON(CH₃)₂, —CH₂NH₂, —CH₂NH(CH₃), —CH₂N(CH₃)₂;R^(1a) is selected from the group consisting of: —H, —F, —Cl and Br;R^(1b) is selected from the group consisting of: —CH₃ and —CF₃; R^(1c1)is selected from the group consisting of: —H, —F, —Cl, —Br, —CN,—CH₂NH₂, —CH₂OH, —CONH₂, —C(NH)NH₂, —CO₂H, —CO₂Me, —SO₂Me, —SO₂NH₂, —OH,—NH₂, and —NO₂; R^(1c2) is selected from the group consisting of: —H,—F, —Cl and —Br; R^(1c3) is selected from the group consisting of: —H,—F, —Cl and —Br.
 13. The following compounds are claimed by the presentinvention:

wherein: R^(1a) is selected from the group consisting of: —H, —F, —Cland —Br; R^(1b) is selected from the group consisting of: —CH₃, —CF₃,—CH₂CH₃, —SO₂Me, —CONH₂ and —NHSO₂Me; R^(1c1) is selected from the groupconsisting of: —H, —F, —Cl, —Br, —NH₂, —OH, —SO₂Me, —SO₂Et, —SO₂NH₂,—NO₂, —CH₂NH₂, —CN, —CONH₂, —CH₂OH; R^(1c2) selected from the groupconsisting of: —H, —F, —Cl, —Br and —OCH₃; R^(1c3) is selected from thegroup consisting of: —H, —F, —Cl, —Br, —OCH₃, —NH₂, —CH₂NH₂, —CONH₂,—CONMe, —CONMe₂.
 14. The following compounds are claimed by the presentinvention:

wherein: A-Q is selected from the group consisting of:

wherein: A is selected from the group consisting of:

R^(1a) is selected from the group consisting of: —H, —F, —Cl and —Br;R^(1c1) is selected from the group consisting of: —H, —F, —Cl, —Br, —CN,—CH₂NH₂, —CH₂OH, —CONH₂, —C(═NH)NH₂, —CO₂H, —CO₂Me, —SO₂Me, —SO₂NH₂,—OH, —NH₂, and —NO₂; R^(1c2) is selected from the group consisting of:—H, —F, —Cl, —Br, and —OCH₃; R^(1c3) is selected from the groupconsisting of: —H, —F, —Cl, —Br, —OCH₃, —NH₂, —CH₂NH₂, —CONH₂, —CONHMe,—CONMe₂; G is selected from the group consisting of:

wherein: R^(1b1) is selected from the group consisting of —H, —CH₃ and—CF₃; R^(1b2) is selected from the group consisting of —H, —CH₃ and—CF₃; R^(1b3) is selected from the group consisting of —Cl, —NH₂, —CH₃and —CF₃.
 15. The following compounds are claimed by the presentinvention:

wherein: R¹ is selected from the group consisting of: —SO₂NH₂, —SO₂CH₃,—CN, —CONH₂, —CONH(CH₃), —CON(CH₃)₂, —CH₂NH₂, —CH₂NH(CH₃), —CH₂N(CH₃)₂;R^(1a) is selected from the group consisting of: —H, —F, —Cl and —Br;R^(1b) is selected from the group consisting of: —H, —CH₃ and —CF₃;R^(1c1) is selected from the group consisting of: —H, —F, —Cl, —Br, —CN,—CH₂NH₂, —CH₂OH, —CONH₂, —C(═NH)NH₂, —CO₂H, —CO₂Me, —SO₂Me, —SO₂NH₂,—OH, —NH₂, and —NO₂; R^(1c2) is selected from the group consisting of:—H, —F, —Cl and —Br; R^(1c3) is selected from the group consisting of:—H, —F, —Cl and —Br.
 16. The following compounds are claimed by thepresent invention:

wherein: R¹ is selected from the group consisting of: —SO₂NH₂, —SO₂CH₃,—CN, —CONH₂, —CONH(CH₃), —CON(CH₃)₂, —CH₂NH₂, —CH₂NH(CH₃), —CH₂N(CH₃)₂;R^(1a) is selected from the group consisting of: —H, —F, —Cl and —Br;R^(1b) is selected from the group consisting of: —H, —CH₃ and —CF₃;R^(1c1) is selected from the group consisting of: —H, —F, —CN, —CH₂NH₂,—CONH₂, —SO₂Me, —SO₂NH₂ and —NO₂; R^(1c2) is selected from the groupconsisting of: —H, —F, —Cl, —Br and —OCH₃; R^(1c3) is selected from thegroup consisting of: —H, —F, —Cl, —Br, —OCH₃, —NH₂, —CH₂NH₂, —CONH₂,—CONHMe, —CONMe₂.
 17. The following compounds are claimed by the presentinvention:

wherein: A-Q is selected from the group consisting of:

wherein: A is selected from the group consisting of:

R^(1a) is selected from the group consisting of: —H, —F, —Cl and —Br;R^(1b) is selected from the group consisting of: —H, —CH₃ and —CF₃;R^(1c1) is selected from the group consisting of: —H, —F, —Cl, —Br, —CN,—CH₂NH₂, —CH₂OH, —CONH₂, —C(═NH)NH₂, —CO₂H, —CO₂Me, —SO₂Me, —SO₂NH₂,—OH, —NH₂, and —NO₂; R^(1c2) is selected from the group consisting of:—H, —F, —Cl and —Br; R^(1c3) is selected from the group consisting of:—H, —F, —Cl and —Br.
 18. The following compounds are claimed by thepresent invention:

wherein: A-Q is selected from the group consisting of:

wherein: A is selected from the group consisting of:

R^(1a) is selected from the group consisting of: —H, —F, —Cl and —Br;R^(1b) is selected from the group consisting of: —H, —CH₃ and —CF₃;R^(1c1) is selected from the group consisting of: —H, —F, —CN, —CH₂NH₂,—CONH₂, —SO₂Me, —SO₂NH₂ and —NO₂; R^(1c2) is selected from the groupconsisting of: —H, —F, —Cl, —Br and —OCH₃; R^(1c3) is selected from thegroup consisting of: —H, —F, —Cl, —Br, —OCH₃, —NH₂, —CH₂NH₂, —CONH₂,—CONHNMe, —CONMe₂.
 19. The following compounds are claimed by thepresent invention:

wherein: R¹ is selected from the group consisting of: —SO₂NH₂, —SO₂Me,—CH₂NH₂ and —CH₂NMe₂; R^(1a) is selected from the group consisting of:—H, —F, —Cl and —Br; R^(1c1) is selected from the group consisting of:—H, —F, —Cl, —Br, —NH₂, —OH, —SO₂Me, —SO₂Et, —SO₂NH₂, —NO₂, —CH₂NH₂,—CN, —CONH₂, —CH₂OH; R^(1c2) and R^(1c3) are independently selected fromthe group consisting of: —H, —F, —Cl and —Br; G is selected from thegroup consisting of:

wherein: R^(1b1) is selected from the group consisting of —H, —CH₃ and—CF₃; R^(1b2) is selected from the group consisting of —H, —CH₃ and—CF₃; R^(1b3) is selected from the group consisting of —Cl, —NH₂, —CH₃and —CF₃.
 20. The following compounds are claimed by the presentinvention:

wherein: R¹ is selected from the group consisting of: —SO₂NH₂, —SO₂Me,—CH₂NH₂ and —CH₂NMe₂; R^(1a) is selected from the group consisting of:—H, —F, —Cl and —Br; R^(1c1) is selected from the group consisting of:—H, —F, —Cl, —Br, —NH₂, —OH, —SO₂Me, —SO₂Et, —SO₂NH₂, —NO₂, —CH₂NH₂,—CN, —CONH₂, —CH₂OH; R^(1c2) and R^(1c3) are independently selected fromthe group consisting of: —H, —F, —Cl and —Br; G is selected from thegroup consisting of:

wherein: R^(1b1) is selected from the group consisting of —H, —CH₃ and—CF₃; R^(1b2) is selected from the group consisting of —H, —CH₃ and—CF₃; R^(1b3) is selected from the group consisting of —Cl, —NH₂, —CH₃and —CF₃.
 21. A pharmaceutical composition for preventing or treating acondition in a mammal characterized by undesired thrombosis comprising apharmaceutically acceptable carrier and a pharmaceutically effectiveamount of a compound of claim
 1. 22. A method for preventing or treatinga condition in a mammal characterized by undesired thrombosis comprisingadministering to said mammal a therapeutically effective amount of acompound of claim
 1. 23. The method of claim 6, wherein the condition isselected from the group consisting of: acute coronary syndrome,myocardial infarction, unstable angina, refractory angina, occlusivecoronary thrombus occurring post-thrombolytic therapy or post-coronaryangioplasty, a thrombotically mediated cerebrovascular syndrome, embolicstroke, thrombotic stroke, transient ischemic attacks, venousthrombosis, deep venous thrombosis, pulmonary embolus, coagulopathy,disseminated intravascular coagulation, thrombotic thrombocytopenicpurpura, thromboangiitis obliterans, thrombotic disease associated withheparin-induced thrombocytopenia, thrombotic complications associatedwith extracorporeal circulation, thrombotic complications associatedwith instrumentation, and thrombotic complications associated with thefitting of prosthetic devices.
 24. A method for inhibiting thecoagulation of biological samples, comprising the step of administeringa compound of claim
 1. 25. A pharmaceutical composition for preventingor treating a condition in a mammal characterized by undesiredthrombosis comprising a pharmaceutically acceptable carrier and apharmaceutically effective amount of a compound of claim
 2. 26. A methodfor preventing or treating a condition in a mammal characterized byundesired thrombosis comprising administering to said mammal atherapeutically effective amount of a compound of claim
 2. 27. Themethod of claim IO, wherein the condition is selected from the groupconsisting of: acute coronary syndrome, myocardial infarction, unstableangina, refractory angina, occlusive coronary thrombus occurringpost-thrombolytic therapy or post-coronary angioplasty, a thromboticallymediated cerebrovascular syndrome, embolic stroke, thrombotic stroke,transient ischemic attacks, venous thrombosis, deep venous thrombosis,pulmonary embolus, coagulopathy, disseminated intravascular coagulation,thrombotic thrombocytopenic purpura, thromboangiitis obliterans,thrombotic disease associated with heparin-induced thrombocytopenia,thrombotic complications associated with extracorporeal circulation,thrombotic complications associated with instrumentation, and thromboticcomplications associated with the fitting of prosthetic devices.
 28. Amethod for inhibiting the coagulation of biological samples, comprisingthe step of administering a compound of claim
 2. 29. A pharmaceuticalcomposition for preventing or treating a condition in a mammalcharacterized by undesired thrombosis comprising a pharmaceuticallyacceptable carrier and a pharmaceutically effective amount of a compoundof claim
 3. 30. A method for preventing or treating a condition in amammal characterized by undesired thrombosis comprising administering tosaid mammal a therapeutically effective amount of a compound of claim 3.31. The method of claim 30, wherein the condition is selected from thegroup consisting of: acute coronary syndrome, myocardial infarction,unstable angina, refractory angina, occlusive coronary thrombusoccurring post-thrombolytic therapy or post-coronary angioplasty, athrombotically mediated cerebrovascular syndrome, embolic stroke,thrombotic stroke, transient ischemic attacks, venous thrombosis, deepvenous thrombosis, pulmonary embolus, coagulopathy, disseminatedintravascular coagulation, thrombotic thrombocytopenic purpura,thromboangiitis obliterans, thrombotic disease associated withheparin-induced thrombocytopenia, thrombotic complications associatedwith extracorporeal circulation, thrombotic complications associatedwith instrumentation, and thrombotic complications associated with thefitting of prosthetic devices.
 32. A method for inhibiting thecoagulation of biological samples, comprising the step of administeringa compound of claim
 3. 33. A pharmaceutical composition for preventingor treating a condition in a mammal characterized by undesiredthrombosis comprising a pharmaceutically acceptable carrier and apharmaceutically effective amount of a compound of claim
 4. 34. A methodfor preventing or treating a condition in a mammal characterized byundesired thrombosis comprising administering to said mammal atherapeutically effective amount of a compound of claim
 4. 35. Themethod of claim 34, wherein the condition is selected from the groupconsisting of: acute coronary syndrome, myocardial infarction, unstableangina, refractory angina, occlusive coronary thrombus occurringpost-thrombolytic therapy or post-coronary angioplasty, a thromboticallymediated cerebrovascular syndrome, embolic stroke, thrombotic stroke,transient ischemic attacks, venous thrombosis, deep venous thrombosis,pulmonary embolus, coagulopathy, disseminated intravascular coagulation,thrombotic thrombocytopenic purpura, thromboangiitis obliterans,thrombotic disease associated with heparin-induced thrombocytopenia,thrombotic complications associated with extracorporeal circulation,thrombotic complications associated with instrumentation, and thromboticcomplications associated with the fitting of prosthetic devices.
 36. Amethod for inhibiting the coagulation of biological samples, comprisingthe step of administering a compound of claim 4.